Gastrointestinal Release Research Articles

Comparative Bioavailability Assessment of Newly Developed Flurbiprofen Matrix Tablets and Froben SR® Tablets in Healthy Pakistani Volunteers

Background: Flurbiprofen is a non-selective cyclo-oxygenase inhibitor, member of series of alkanoic acid derivatives, has anti-inflammatory, analgesic activity. Also used to treat gout, osteoarthritis, rheumatoid arthritis and is effective in inhibiting surgically induced miosis in human eyes while cataract extraction. Oral sustained release formulation as a novel matrix system of flurbiprofen tablets were prepared using Carboxy methylcellulose as release retardant. Objective: The aim of present study was comparative bioavailability assessment of newly developed flurbiprofen matrix tablets for sustained delivery, with commercially available Froben SR. Methods: Randomized, open-label, 2-periods, cross-over study conducted on 24 male healthy volunteers in Pakistan. Small batch of flurbiprofen matrix tablets were manufactured and evaluated according to Pharmacopoeial specifications. Each volunteer received a 200-mg tablet of the test and reference formulations, separated by a 7-day washout period. Blood samples were obtained before dosing 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, and 24 hours after drug administration. Safety monitoring was performed which includes adverse events. Plasma concentrations of the 2 formulations were determined, and pharmacokinetic parameters were compared using noncompartmental analysis. In-vivo disposition kinetics was evaluated using single dose, cross over, complete two period of treatment design in twenty four healthy male human volunteers; the drug was assayed in plasma using HPLC-UV detection, and results were compared. Various pharmacokinetic parameters (Cmax, Tmax, area under the curve [AUC0-24], mean residence time) and relative bioavailability were compared. Results: No significant differences were found for Cmax, Tmax,AUC and other parameters. The rate and extent of drug release from matrix tablets was not significantly different from commercially available Froben SR tablets. An in vivo result indicates prolonged blood levels with delayed peak and comparable bioavailability. Conclusions: The matrix tablets could also provide, sustained, gastrointestinal environmentalindependent release that may result in an improved therapeutic efficacy.

Pharmacokinetics, bioequivalence, tolerability, and effects on platelet counts of two formulations of anagrelide in healthy volunteers and patients with thrombocythemia associated with chronic myeloproliferation

Background: Anagrelide hydrochloride is an anti-thrombotic agent indicated for the treatment of essential thrombocythemia (ET). In various previously published clinical trials of 2 branded formulations of anagrelide in patients with ET at high risk for thrombohemorrhagic events, the rates of adverse events and discontinuation were strikingly divergent between brands. Because the formulations and manufacturers differed, the differences in tolerability, as well as platelet counts, might have been related to differences in pharmacokinetic properties between the 2 formulations. Objectives: The present series of investigations (1) determined the pharmacokinetic profile of anagrelide and its metabolites; (2) compared the pharmacokinetic profiles of the test and reference formulations of anagrelide; (3) investigated the in vitro release of anagrelide as a marker of intragastric anagrelide release of the test and reference formulations; and (4) compared the platelet-reducing effects of the test and reference formulations in patients with thrombocythemia in 2 longitudinal studies over 4 weeks. Methods: A series of 4 in vivo studies and 1 in vitro study were conducted. In a pilot, prospective, singledose study in healthy volunteers, the pharmacokinetic properties (C max, T max, and AUC 0-∞) of a test formulation of anagrelide were assessed using high-performance liquid chromatography analysis of plasma samples. Based on the results from that study, a single-dose, randomized, double-blind, 2-period crossover study in healthy volunteers was conducted to determine bioequivalence of 2 formulations of anagrelide 2 mg/d (taken as 4 capsules). In vitro dissolution properties of the test or reference formulation containing 0.5 mg anagrelide as the active ingredient were studied in an assay mimicking gastrointestinal release. To test for effects on platelet counts of switching from the reference formulation (previous treatment on stable dose for 3 months) to the test formulation, two 4-week longitudinal trials were conducted: one in patients with ET (in Germany), and one in patients with thrombocythemia associated with chronic myeloproliferative disorders (CMPDs) (in Austria). Results: The pilot pharmacokinetic study of the test formulation in 16 volunteers (10 women, 6 men; mean [SD] age, 20.5 [1.5] years; weight, 69.0 [10.0 kg) suggested that anagrelide was metabolized to 3-hydroxyanagrelide (AUC 0-∞ 50% compared with anagrelide) and the inactive metabolite 2-amino-5,6-dichloro-,4-dihydroquinazolone. The subsequent bioequivalence study in 24 volunteers (14 women, 10 men; mean [SD] age, 23 [4] years; white, 100%; weight, 67.5 [10.2] kg) found that the test formulation was associated with a significantly lower C max (point estimation [PE], 66%; 90% CI, 58%-76%; P < 0.001) and AUC 0-∞ (PE, 77%; 90% CI, 68%-86%; P = 0.001). T max values for anagrelide and 3-hydroxyanagrelide were 1 hour longer with the test formulation compared with the reference formulation. The total number of adverse events with the reference formulation was 46; the test formulation, 29 ( P = 0.05). In vitro, anagrelide from the reference formulation was immediately released (89.1% at 5 minutes), whereas there was a delayed release (93.6% at 30 minutes) from the test formulation ( P < 0.05). In the last 2 studies, 2 cohorts of white patients (cohort 1, 15 patients with ET; 10 women, 5 men; mean [SD] age, 49.0 [10.7] years [range, 31-66 years]; weight, 73.2 [12.6] kg; cohort 2, 19 patients with thrombocythemia associated with CMPD; 12 women, 7 men; age, 62.6 [12.4] years [range, 38-80 years]; weight, 66.1 [13.3] kg) who had received treatment for ≥3 months with the reference formulation were switched to the same dose of the test formulation and maintained on this dose for 4 weeks. Platelet counts did not change significantly from baseline over 4 weeks and stayed within a predefined margin of 150 × 10 3 cells/μL. Conclusions: The pharmacokinetic properties, adverse event rates, and in vitro dissolution profile differed between the test and reference anagrelide formulations in these healthy volunteers. In patients with ET or thrombocythemia associated with CMPD, platelet counts did not differ significantly from baseline at 4 weeks when subjects were switched from the reference to the test anagrelide formulation.

Insulin-Loaded Nanoparticles are Prepared by Alginate Ionotropic Pre-Gelation Followed by Chitosan Polyelectrolyte Complexation

Alginate nanoparticles were prepared from dilute alginate sol by inducing a pre-gel with calcium counter ions, followed by polyelectrolyte complex coating with chitosan. Particles in the nanometer size range were obtained with 0.05% alginate and 0.9 mM Ca2+. The mean particle size was influenced by time and stirring speed of nanoparticle preparation, by alginate guluronic acid content and chitosan molecular weight and by the initial alginate:chitosan mass ratio. The association efficiency of insulin into alginate nanoparticles, as well as loading capacity were mainly influenced by the alginate:chitosan mass ratio. Under optimized size conditions, the association efficiency and loading capacities were as high as 92% and 14.3%, respectively. Approximately 50% of the protein was partially retained by the nanoparticles in gastric pH environment up to 24 hours while a more extensive release close to 75% was observed under intestinal pH conditions. Mild formulation conditions, optimum particle size range obtained, high insulin entrapment efficiency, and resistance to gastrointestinal release seem to be synergic and promising factors toward development of an oral insulin delivery form.

Serotonin-3 receptors in gastric mechanisms of cholecystokinin-induced satiety

our understanding of the controls of food intake has increased substantially during the last 30 years. Important in this has been the recognition of the meal as a controlled, physiologically relevant unit of energy intake. During a meal, ingested nutrients accumulate in the stomach and gradually

Colonic Drug Delivery: Influence of Cross-linking Agent on Pectin Beads Properties and Role of the Shell Capsule type

ABSTRACTFor colonic delivery, pectin beads obtained by ionotropic gelation method have been already reported as an interesting approach. This study investigated the influence of the cross-linking agent (calcium or zinc) and the type of shell capsule used (classical or enteric capsules) on pectin beads properties and on their performance to target the colon (in vitro dissolution studies with subsequent pH change to mimic overall gastro-intestinal tract). Zinc pectinate beads seemed to be relatively similar to calcium's ones in morphological point, except on the surface aspect. When beads were introduced in classical hard capsules, ketoprofen release was not significantly different between CPG and ZPG beads, and it was too premature and too quick due to a chemical erosion of the pectinate matrix (acid + basic attacks). However, zinc pectinate beads showed slower ketoprofen release compared with calcium pectinate beads when enteric hard capsules were used. This interesting finding could be due to the strength of the network formed during the process between the zinc cations and the LM-pectin following the “egg-box” model. This network was stronger and induced a reduction of swelling and hydration when contact with dissolution medium, then subsequently a decrease of drug release. Thus, the zinc pectinate beads could protect sufficiently drug entrapped from the upper gastro-intestinal conditions and drug release will be controlled by pectin degradation with colonic microflora. Finally, these zinc pectinate beads in enteric hard capsules are promising as a carrier for specific colonic delivery of drugs after oral administration.

The effects of medetomidine and xylazine on gastrointestinal motility and gastrin release in the dog.

The effect of medetomidine, a potent and highly selective alpha2-adrenoceptor agonist, on the motility of the gastric antrum, duodenum, mid-jejunum and ileum was investigated in ten dogs. Its effect on the release of gastrin was also determined. Administration of medetomidine intramuscularly (i.m.) at a dose of 40 microg/kg inhibited the motility of the gastric antrum, duodenum, mid-jejunum and ileum significantly, in comparison to administration of xylazine intramuscularly at a dose of 2.0 mg/kg. The release of gastrin was also significantly decreased in dogs receiving medetomidine. It was found to inhibit the motility in the gastric antrum and duodenum longer than in the mid-jejunum and ileum, presumably by acting specifically on alpha2-adrenoceptors, likely at the peripheral level. Medetomidine also inhibited the gastric contraction associated with gastrin secretion.

Myocardial and gastrointestinal release of vasoactive intestinal peptide during experimental acute myocardial infarction.

Vasoactive intestinal peptide (VIP) acts as a vasodilator on coronary and gastrointestinal arteries. During coronary occlusion, the locally released VIP may exert a protective effect on the heart, but it may aggravate the shock state through its vasodilatory effect in the gastrointestinal tract. After left thoracotomy, the left circumflex coronary artery (LCx) was prepared, and a pneumatic occluder was introduced around it. After 60 min of coronary occlusion, the LCx was reperfused in six dogs (reperfusion group), while in another six the occlusion was maintained for 6 h (occlusion group). Five dogs served as sham-operated controls. The plasma concentration of VIP was determined at baseline, after the 60 min occlusion and 10 min, 3 h and 6 h after reperfusion, or 3 h and 6 h after continuous occlusion in the coronary sinus and in the femoral and portal veins. The plasma VIP concentrations in all three vessels were increased after 60 min of LCx occlusion. During the 6 h constant coronary occlusion, concentrations remained increased in both the coronary sinus and the portal vein, but not in the femoral vein. In the reperfusion group, 10 min after reperfusion, the plasma concentrations of VIP in all three vessels had decreased. Coronary artery occlusion causes a long-term increase in plasma VIP concentrations that decreases after reperfusion, when measured in the portal vein and coronary sinus, but not in the femoral veins.

Effects des protéines laitières sur l'absorption de Ca et P mesurée par les variations temporelles de leurs teneurs dans l'aorte et la veine porte chez le rat

Cette étude visait à mettre en évidence la relation qui peut exister entre les différentes protéines du lait et de soya et l'absorption du calcium (Ca) et du phosphore (P). A cette fin, des rats mâles de la lignée Sprague-Dawley ont eu libre accès pendant 10 jours, à huit diètes protéiques entièrement équilibrées avec lait, lactosérum, caséine, β-caséine, α-lactalbumine, β-lactoglobuline ou soya. Au 10ième jour, des prélèvements de sang au niveau portal et aortique ont été faits sur des rats anesthésiés après 0, 3, 6 et 12 h du début de la période de prise alimentaire maximale, afin d'évaluer l'absorption du Ca et du P par la méthode des différences portoaortiques. Pour tous les groupes, on a noté un accroissement significatif ( P < 0·01) et équivalent du poids corporel et une efficacité de conversion protéique comparable. Quelque soit le site de prélèvement portal ou aortique, les teneurs en Ca et P ont été significativement affectées par les diètes ( P < 0·05) et le temps d'échantillonnage ( P < 0·05). Des différences portoaortiques significativement différentes de zéro ( P < 0·05) ont été observées à divers moments dans chaque groupe. Les diètes à base de lait et de ses fractions protéiques ont donné un maximum d'adsorption de Ca après 6 h, comparativement à 12 h pour le soya; l'α-lactalbumine étant supérieure aux autres protéines. Dans le cas du P, les résultats ont été beaucoup plus variables, les caséines montrant némoins une supériorité par rapport aux autres sources protéiques. Ces résultats sont expliqués par l'influence des processus de digestion et la libération, en fonction du temps et des sources protéiques, de différents sous-produits, peptides et acides aminés, qui agissent, soit sur la solubilisation des éléments minéraux, soit sur des mécanismes reliés à leur absorption rapide ou lente, dans l'intestin proximal ou distal par des systèmes de transport actif ou passif. The effects of milk and soya dietary proteins on plasma calcium and phosphorus levels in aorta and portal veins were investigated. Sprague-Dawley rats were fed ad libitum with equilibrated milk protein based diets containing milk, whey, caseins, α s -casein, β-casein, α-lactalbumin, β-lactoglobulin or soya. On the 10th day, animals on each diet were anesthetized with halothane and blood samples were collected from the aorta and portal veins 0, 3, 6 and 12 h after the onset of the active eating period. Calcium and phosphorus were determined in these blood samples and portoaortic differences were calculated. There was a significant ( P < 0·01) and equivalent increase in body weight and comparable Protein Efficiency Ratio (PER) in all groups. Whatever the site of sample collections, the calcium and phosphorus concentrations were significantly ( P < 0·05) altered by protein diets and sampling time. Significant ( P < 0·05) portoaortic differences higher than zero were found in all groups, but at various sampling times, indicating that the kinetics of intestinal absorption were dependent on the protein fed. Milk protein-fed groups showed maximum absorption of Ca after 6 h, compared to 12 h for the soya fed group; the α-lactalbumin-fed group had higher Ca absorption. Phosphorus results were variable, but the casein fed group showed the highest significant portoaortic differences compared to all other groups. These results can be explained by the digestion processes involved and the gastro-intestinal release, as a function of time and protein sources, of amino acids and peptides which may affect either mineral solubility, or the fast and slow mechanisms of their absorption located respectively in the proximal and distal parts of the intestine.

Effectiveness and long-term tolerability of the slow release oral form of bromocriptine on tumoral and non-tumoral hyperprolactinemia

The effectiveness and long-term tolerability of a new formulation of bromocriptine with slow gastrointestinal release (Parlodel SRO) has been evaluated on ten patients with macroprolactinoma, seven patients with microprolactinoma and five patients with nontumoral hyperprolactinemia during a period of 1-30 months. Six out of ten macroprolactinoma-bearing patients obtained a rapid normalization of plasma PRL levels with reduction of the tumor size recorded by CT scan follow-up. Four of six microprolactinomas and all the five nontumoral hyperprolactinemic patients became normoprolactinemic with recovery of gonadal functions while in two other microprolactinomas Parlodel SRO significantly reduced plasma PRL levels with restoration of menses. Only in two patients the treatment was withdrawn for the appearance of side effects. In conclusion, Parlodel SRO is an effective drug in the management of tumoral and nontumoral hyperprolactinemia. The good long-term tolerability together with the hypoprolactinemic activity makes this drug a very good choice therapy in hyperprolactinemic syndromes even in case of poor tolerability to the standard formulation of the drug.

Inhibition of gastrointestinal release of acetylchoune byquercetin as a possible mode of action of Psidium guajava leaf extracts in the treatment of acute diarrhoeal disease

The electrically stimulated guinea-pig ileum and spontaneously contracting guinea-pig ileum preparations were employed in studies on the effects of an alcoholic extract and two flavonoid compounds, quercetin and quercetin-3-arabinoside, extracted from the leaves of Psidium guajava. The extract showed a morphine-like inhibition of acetylcholine release in the coaxially stimulated ileum, together with an initial increase in muscular tone, followed by a gradual decrease. The morphine-like inhibition was found to be due to quercetin, starting at concentrations of 1.6 μg ml . The glycoside did not show any such action at concentrations of up to 1.28 mg ml . The extract inhibited spontaneous contractions in the unstimulated ileum with a concentration-response relationship.

Gastro-intestinal bioavailability assessment of commercialy prepared sustained-release lithium tablets using a deconvolution technique

AbstractThe bioavailability of a commercial formulation of sustained release Lithium, containing 10.4 mM in the form of carbonate per tablet, was evaluated by a bioequivalency assay using 10 healthy volunteers. As reference, gelatine capsules containing the same dosage were used. By numerical deconvolution of the mean urinary excretion curves an equation representing the amounts of Lithium released in the gastrointestinal tract was obtained, proving equal to 1.0 + 0.94.t - 0.012.t, 0 ! t ! 8 hours. This results were confirmed by the Bayesian interpretation of the bioequivalency study, with acceptability intervals determined for each parameter used, total amount of lithium excreted in the urine and maximum urinary excretion rate. The limits were established from the curves obtained under simulation using the absorption-disposition parameters of the urinary excretion curve and optimum gastrointestinal release Kinetics. The results suggest that the bioavailability of the tablets is moderately reduced as the ...

Role of nutrients in the gastrointestinal release of immunoreactive neurotensin

Neurotensin is a brain-gut tridecapeptide. It can be released into the circulation upon ingestion of a meal, or when the jejuno-ileal segment of the human gut is exposed to a mixed meal. Among the various constituents of the products of food digestion, fatty acid is the most potent in stimulating immunoreactive neurotensin release. This response is dose dependent. The physiological role of postprandial changes of circulating neurotensin needs further elucidation.