Investigation of the Gastrointestinal Transit and In Vivo Drug Release of Isosorbide-5-Nitrate Pellets

An oral formulation of controlled-release isosorbide-5-nitrate pellets has been used to investigate the location of pellets in the gastrointestinal (GI) tract and, in parallel, to measure the drug absorption from these locations. Using the method of gamma scintigraphy the transit times and spreading of pellets in the GI tract have been determined. The method of numeric deconvolution was applied to calculate the drug input into the systemic circulation. The results indicate that a well-absorbed substance such as isosorbide-5-nitrate is absorbed from the stomach and small intestinal in a manner that is controlled by the properties of the pellets. Drug absorption is reduced in the colon. The average transit time from mouth to colon is 6 to 8 hr, which represents the maximum acceptable time for drug release for this oral controlled-release preparation. Taking into account these relations an isosorbide-5-nitrate pellet formulation with a bioavailability of 84% has been developed that maintained the minimal therapeutic plasma level for more than 16 hr after application.     

In-vitro and in-vivo studies of pectin/ethylcellulosefilm-coated pellets of 5-fluorouracil for colonic targeting

The aim of the present study was to define in-vitro and in-vivo characteristics of pectin/ethylcellulose-film-coated pellets of 5-fluorouracil (5-FU) for colonic targeting. The pellet cores were coated to different film thicknesses with three different pectin/ethylcellulose formulations using a fluidized bed coater. The gastrointestinal (GI) transit of coated pellets was determined by counting the percentage of coated pellets in the GI lumen by celiotomy at certain times after oral administration. 5FU was administered to rats at a dose of 15 mg kg(-1). The toxicity of 5-FU in the GI tract was evaluated using histological examination. The 1:2 ratio pectin:ethylcellulose-coated pellets with 30% total weight gain (TWG-30%) produced more satisfactory drug-release profiles in the simulated gastric, intestinal and colonic fluids. Most of the coated pellets were eliminated from the stomach in 2 h, moved into the small intestine after 2-4 h, and reached the large intestine after 4 h. After oral administration of coated pellets, 5-FU started appearing in the plasma at 7 h, and reached peak plasma concentration (Cmax) of 3.21+/-2.01 microg mL(-1) at 16 h (Tmax); the Cmax for uncoated pellets was 22.21+/-2.60 microg mL(-1) at Tmax 0.75 h. The TWG-30% formulation showed delayed Tmax, decreased Cmax and prolonged mean residence time compared with uncoated pellets. Marked pathological features in the colon were seen in rats given coated pellets, but no injuries were observed in the upper GI tract. The formulation of TWG-30% could deliver 5-FU to the colon for local action.     

Distribution of pellets in the gastrointestinal tract. The influence on transit time exerted by the density or diameter of pellets.

The influence on transit time exerted by the density or diameter of pellets has been established in six ileostomy subjects. An increase in density from 1.0 to 1.6 significantly increased the average transit time of pellets in the small intestine. The average transit time for the light and heavy pellets being 7 and 25 h respectively. The diameter of pellets is of minor significance. The findings suggest the use of density as a means of modifying the period of absorption of controlled-release pellets.     

Gastrointestinal transit of a controlled-release pellet formulation of tiaprofenic acid and the effect of food

The gastrointestinal transit of a controlled-release pellet formulation of tiaprofenic acid has been studied in human subjects. The pellets were labelled with a gamma-emitting radionuclide and their gastric emptying and colon arrival profiles monitored using a gamma camera after two different feeding conditions; light breakfast and heavy breakfast. It is clearly demonstrated that feeding has an important effect upon the gastrointestinal transit profiles. The presence of the heavy breakfast causes a lengthened gastrointestinal time and also a greater spreading of the pellets within the small intestine. As has been found previously, the transit time of the pellets (expressed as time for 50%) to move from pyloric sphincter to ileocaecal sphincter was of the order of 3 h and was independent of the nature of the meal provided.     

Gastro-intestinal transit of a multiple-unit formulation (metoprolol CR/ZOK) and a non-disintegrating tablet with the emphasis on colon

The main aim of the present study was to compare the transit through the entire gastro-intestinal channel of a membrane-coated, multiple-unit system containing metoprolol and a single-unit placebo tablet using gamma-scintigraphy. The two formulations were simultaneously administered, together with a breakfast (2800 kJ), to eight healthy male volunteers. The mean gastric emptying time for the pellets was 3.6 (range 1.5–5.0) h on average and the mean gastric emptying time for the tablet was 9.6 (range 3.3-(14–24)) h. This difference was statistically significant. The mean transit through the small intestine, 3.1 (range 1.5–5.7) h and 2.0 (range 1.0–3.3) h for the pellets and the tablet respectively, did not differ significantly between the formulations. The pellets had a longer residence time in the colon in all subjects compared with the tablet. The mean colon transit time was 28 (range 6.0–48) h on average for the pellets and 15 (range 3.8–26) h for the tablet. The tablet was expelled 26 (range 9.5–42) h after intake on average, whereas the pellets remained for a significantly longer time period (mean 35, range 10–55 h). The desired extended-release properties and metoprolol absorption was obtained throughout the entire gastrointestinal (GI) tract.     

Distribution of pellets in the gastrointestinal tract. The influence on transit time exerted by the density or diameter of pellets

The influence on transit time exerted by the density or diameter of pellets has been established in six ileostomy subjects. An increase in density from 1·0 to 1·6 significantly increased the average transit time of pellets in the small intestine. The average transit time for the light and heavy pellets being 7 and 25 h respectively. The diameter of pellets is of minor significance. The findings suggest the use of density as a means of modifying the period of absorption of controlled-release pellets.     

The use of formulation technology to assess regional gastrointestinal drug absorption in humans.

The aim of this study was to assess the feasibility of using oral modified-release formulations for the purposes of site-specific targeting and regional drug absorption assessment in man. An immediate release pellet formulation containing ranitidine as the model drug of choice for the study was fabricated by extrusion-spheronisation, and then film coated with either the enteric polymer polyvinyl acetate phthalate or the bacteria-degradable polymer amylose, in combination with ethylcellulose, to effect drug release within the small intestine and colon, respectively. Optimised formulations were evaluated in vivo in ten healthy volunteers, who each received, on four separate occasions, the immediate release, small intestinal release and colonic release formulations (each equivalent to 150mg ranitidine), and an intravenous injection of ranitidine (equivalent to 50mg ranitidine). Blood samples were collected and assessed for ranitidine concentration, and radiolabelled placebo pellets were co-administered with the coated ranitidine pellets to monitor their gastrointestinal transit using a gamma camera. Ranitidine was rapidly released and absorbed from the immediate release formulation, whereas the enteric formulation (10% coat weight gain) delayed drug release until some or all of the pellets had emptied into the small intestine. The amylose-ethylcellulose coated formulation (coat ratio 1:3, coat weight gain 25%) retarded ranitidine release until the pellets had reached the colon. The mean absolute bioavailability of ranitidine from the immediate release, small intestinal release and colonic release formulations were 50.6, 46.1 and 5.5%, respectively. These data are in general agreement to those obtained from a previous regional intubation study. The present study therefore demonstrates the practical potential of utilising a non-invasive, formulation-based approach to assess drug absorption from different regions of the human gastrointestinal tract.     

The effect of food on the gastrointestinal transit of pellets and an osmotic device (Osmet)

The gastrointestinal transit of a pellet formulation and an osmotic pump device (Osmet) has been evaluated in 6 subjects using the technique of gamma scintigraphy. The two formulations were labeled with different radionuclides so that they could be monitored concurrently. The transit from the stomach through the small intestine to the colon was influenced by the nature of the meal taken shortly before dosing. On a light breakfast the pellets and osmotic devices were emptied quite rapidly. However, following a heavy breakfast the pellets were emptied more slowly while the osmotic devices were retained in the stomach for approximately 10 h. Transit behaviour is discussed in terms of the known physiological determinants of gastrointestinal motility and the concept of the ‘reserve length’ for drug absorption.     

A site-specific controlled-release system for metformin

Oral absorption of the antihyperglycaemic agent metformin hydrochloride (MF-HCl) is confined to the upper part of the intestine, therefore rational controlled-release formulations of this drug should ensure a complete release during transit from stomach to jejunum. The aim of this study was the preparation of a system able to sustain release of high MF-HCl doses in compliance with the above requirement. Matrices (6 mm diameter; 50 mg weight) comprising varying drug-Precirol ATO 5 ratios were prepared by compression. The matrix containing 70% drug was coated on one face with Eudragit L100-55. Drug release to simulated gastric (SGF), jejunal (SJF) and ileal (SIF) fluids in sequence was studied using a modified USP rotating basket method. Release depended on drug load whereas it was independent of dissolution medium pH and hydrodynamics. Release kinetics were of radical t type and were determined by drug diffusion in aqueous pores created in the matrix by drug dissolution. An equation correlating rate-determining factors was developed, whereby the release pattern could be optimized. The half-coated matrix started release in SGF and completed it in SJF. The half-coated matrix, synchronizing drug release and matrix transit across the small intestine, may improve drug bioavailability and reduce side effects.     

Correlation of Phenylpropanolamine Bioavailability with Gastrointestinal Transit by Scintigraphic Monitoring of 111In-Labeled Hydroxypropylmethylcellulose Matrices

Two controlled-release hydroxypropylmethylcellulose (HPMC) matrix formulations, a single-unit and a multiple-unit system, have been evaluated in human volunteers. Both formulations contained the sympathomimetic drug phenylpropanolamine hydrochloride and each was radiolabeled with ¹¹¹Inbound Amberlite IR 120 ion-exchange resin. The formulations were administered to each of six healthy male volunteers and gastrointestinal (GI) transit was monitored using a gamma camera. Serum samples were taken at set time intervals and assayed for phenylpropanolamine content, thus allowing blood drug levels to be correlated with the position of the dosage form in the GI tract. The multiple-unit system emptied from the stomach gradually over a period of about 180 min, when administered after a light breakfast, whereas the single-unit dosage forms had extremely variable gastric emptying times (range, 60 to >570 min). However, both formulations provided prolonged phenylpropanolamine blood levels. The differences in the blood profiles obtained with the two formulations were attributed to variations in their in vitro release rates and not to any differences in their GI transit times.     

Comparison of the mechanical destructive force in the small intestine of dog and human

The purpose of this study was to evaluate the destructive force that oral solid dosage forms receive in the small intestine of dogs and humans. Information on the mechanical destructive forces of the gastrointestinal tract (GI) helps formulation design research in the following way: (1) to improve the predictability of the dissolution test since in vivo drug release is affected by not only agitation intensity but also mechanical stress; (2) to design safe and robust products by avoiding dose-dumping or unintended drug release at an inadequate site; (3) to better understand the species difference in bioavailability by comparing the destructive forces against dosage forms in the GI of dogs with those of humans. "Destructive force Dependent Release System" (DDRS) was developed to measure the mechanical destructive forces of the GI tract by using highly hydrophobic Teflon powder. In a DDRS, a marker drug contained in the core tablet is released only when the DDRS receives a force larger than its pre-determined crushing strength. DDRS-Small Intestine (DDRS-SI), a modified DDRS, was prepared for targeting the small intestine. DDRS-SI was encapsulated in starch capsules (Capill) and then the capsules were coated with an enteric film (DDRS-SI-Ecap). The capsules were administered to six dogs and nine human volunteers. Both dogs and human volunteers crushed a DDRS-SI having a crushing strength of 1.2 N. Therefore, these controlled-release formulations should withstand a destructive force of 1.2 N when they pass through the small intestine.     

The relationship between gastrointestinal transit and motility in dogs with postoperative ileus

We investigated the relationship between gastrointestinal (GI) transit and motility during postoperative ileus in dogs undergoing a single laparotomy. We combined X-ray radiography for a GI transit study with chronically implanted force transducers (FTs) for a GI motility study. Radio-opaque markers made of polyethylene and steel wires or barium sulfate were used to examine solid substance transit or liquid substance transit. For a while after the end of the operation, postoperative ileus was observed, with weak irregular contractions of the GI tract. Transmission of the contractions to the lower GI tract was then observed. The start point of interdigestive migrating contraction (IMC)-like motility was observed in the order of small intestine (I-IMC), duodenum (D-IMC), and stomach (G-IMC), and IMC proceeded gradually after the operation. The gastric emptying time of a solid marker was 73.6 +/- 2.3 h (n = 5), and depended on the time of first occurrence of G-IMC (r = 0.674, p = 0.006). The gastric emptying of the liquid marker was finished before the time of the first occurrence of G-IMC, and its small intestinal transit time correlated with the time of the first occurrence of G-IMC (r = 0.888, p = 0.018). Using combined X-ray radiography and FTs we found that recovery from postoperative ileus was aided by GI motility in which contractions were transmitted from the stomach to the lower GI tract, like IMC.     

Gastrointestinal Transit of Nondisintegrating,Nonerodible Oral Dosage Forms in Pigs

Gastrointestinal (GI) transit data necessary as baseline or control information were collected using pigs as animal models preliminary to bioavailability studies of new sustained action formulations. Density and size effects of nondisintegrating dosage forms on GI transit were investigated. Initially, enteric-coated nondisintegrating magnesium hydroxide caplets (density, 1.5 g/ml; size, 19.6 × 9.5 mm; weight, 1.2 g) were utilized in seven pigs. Prolonged gastric residence (>5 days) occurred in every case for this dosage form. Therefore, nondisintegrating caplets of three densities (1.25, 1.45, and 2.3 g/ml) and three different sizes (large, 20 × 10 mm; medium, 10 × 10 mm; small, 5 × 10 mm) were studied in two more pigs. Roentgenography was used to visualize passage of caplets through the GI tract. Heidelberg pH capsules (size, 8 × 20 mm; density, 1.61 g/ml) were also used in this study. Total GI transit times range from 2 to 33 days for 22 administrations of these nondisintegrating dosage forms. Pigs are found to not be an appropriate model for evaluating bioavailability of nondisintegrating controlled-release dosage forms because total GI transit time (especially gastric transit) is much too long.     

THEOPHYLLINE CONTROLLED-RELEASE FORMULATIONS: IN VIVO--IN VITRO CORRELATIONS

Four experimental controlled-release oral solid dosage formulations were developed and the in vitro dissolution characteristics of theophylline from these formulations were studied in USP apparatus I. Pharmacokinetic evaluation of these formulations was carried out in eight beagle dogs under fasting conditions. Theophylline in a 5% dextrose injection USP, oral solution, and Slo-Phyllin® were used as controls to estimate the in vivo dissolution of these four formulations in the GI tract. The percentage cumulative amounts of drug absorbed and the percentage cumulative amounts of drug released into the GI tract from these four controlled-release formulations were obtained by numerical deconvolution methods. The in vivo and in vitro dissolution data demonstrated good correlation indicating that in vitro dissolution tests can be used to optimize the further design of controlled drug release oral solid dosage formulations for theophylline.     

Leaky enteric coating on ranitidine hydrochloride beads: Dissolution and prediction of plasma data.

The present research is based on the hypothesis that leaky enteric-coated pellets formulations are able to provide sustained input for drugs that have an absorption window, such as ranitidine hydrochloride, without jeopardizing their bioavailability. Leaky enteric-coated pellets formulations are defined as enteric-coated pellets that allow some of the drug to be released from the formulation in gastric fluid. Different approaches to making leaky enteric-coated pellets were investigated using extrusion-spheronization followed by spray coating. Leaky enteric coats were formulated using a commonly used enteric polymer, Eudragit((R)) L 30 D-55, combined with soluble compounds including lactose, PEG 8000 and surfactants (Span 60 (hydrophobic) or Tween 80 (hydrophilic)). The rate of drug release from the formulations in simulated gastric fluid can be tailored by varying the additive's amount or type. All leaky enteric-coated formulations studied completely released the drugs within 30min after changing dissolution medium to phosphate buffer, pH 6. Predictions of plasma concentration-time profiles of the model drug ranitidine hydrochloride from leaky enteric-coated pellets in fasted conditions and from immediate-release formulations were performed using computer simulations. Simulation results are consistent with a hypothesis that leaky enteric-coated pellets formulations provide sustained input for drugs shown to have an absorption window without decreasing bioavailability. The sustained input results from the combined effects of the formulation and GI transit effects on pellets. The present research demonstrates a new application of knowledge about gastrointestinal transit effects on drug formulations. It also shows that enteric-coating polymers have new applications in areas other than the usual enteric-coated formulations. The hypothesis that a leaky enteric-coated pellets formulation may maintain or increase the bioavailability of drugs that have a window of absorption is still to be confirmed by further in vivo studies.     

Preparation of Controlled-Release Coevaporates of Dipyridamole by Loading Neutral Pellets in a Fluidized-Bed Coating System

Purpose. The purpose of this study was to demonstrate that it is possible to prepare controlled-release drug-polymer coevaporates on an industrial scale, omitting the recovery problems and the milling and sieving processes encountered when coevaporates are prepared by the conventional solvent-evaporation technique. Methods. Controlled-release coevaporates were prepared by spraying organic solutions of dipyridamole-Eudragit^® blends onto neutral pellets using the fluidized-bed coating method. Enteric acrylic polymers Eudragit^® L100-55, L, and S were used as dispersing agents and drug/polymer ratio 2:8 was selected for all formulations. Polarized light microscopy, X-ray diffraction spectroscopy, and differential scanning calorimetry were used to determine whether the drug was amorphous or crystalline in the coating films. Moreover, in vitro dissolution tests were performed on the dipyridamole coated pellets in test media simulating the pH variations in the GI tract and the results were compared to the release data obtained from coevaporates prepared by the conventional solvent-evaporation method. Results. All the results clearly indicate that dipyridamole is amorphous in the coating films deposited on neutral pellets as well as in coevaporate particles obtained by the conventional solvent-evaporation method. When the release patterns of the dipyridamole coated pellets are compared to those of the drug coevaporate particles prepared with the same enteric acrylic polymers, the results show similar dissolution trends. Conclusions. The results obtained indicate that pelletization can be considered as a method of choice for pilot plant and/or full-scale production of controlled-release dosage forms based on the formation of amorphous solid dispersions.     

The effect of food on the movement of pellets in the gastro-intestinal tract

The effect of food on the movement of pellets in the gastro-intestinal tract was investigated in seven volunteers, either by means of X-rays taken after oral administration of barium sulfate pellets or by means of saliva concentration profiles of lithium obtained after oral administration of lithium sulfate controlled-release pellets. The X-ray studies showed that food had an effect on the time required for the pellets to leave the stomach and on their degree of dispersion in the small intestine, but not on other parameters. The studies with the lithium sulfate controlled-release pellets showed that food had a significant effect only in one in three subjects.     

Gastrointestinal transit and mucoadhesive characteristics of complexation hydrogels in rats

The aim of this study was to investigate the gastrointestinal (GI) transit and mucoadhesive properties of complexation hydrogels, poly(methacrylic acid-grafted-ethylene glycol). The fluorescent labeled complexation hydrogels containing different molar ratios of methacrylic acid/ethylene glycol and different particle diameters were synthesized by free radical solution polymerization. The GI transit profiles of microparticles after oral administration to rats were evaluated by determining the polymer remaining in the stomach and the small intestine. Moreover, the mucoadhesion to the duodenal mucosa was evaluated by an in situ perfusion method. The ethylene glycol content and particle size of the hydrogels influenced significantly the GI transit and mucoadhesive capacities. The microparticles composed of polymers prepared from 1:1 ratio of methacrylic acid/ethylene glycol and having diameters of <53 microm showed the strongest mucoadhesive capacity. These findings indicated that the hydrogels may be a promising tool for improving oral bioavailability of various drugs, which are poorly absorbed from the GI tract.     

Preparation and characterization of controlled-release doxazosin mesylate pellets using a simple drug layering-aquacoating technique

Pellets are one of multiparticulate pharmaceutical forms and can offer numerous technical and biopharmaceutical advantages compared with single dose unit formulations, e.g. tablets and capsules. This study aimed at formulation of controlled-release pellets of doxazosin mesylate (DM), a widely used treatment for antihypertensive and benign prostatic hyperplasia. DM was loaded onto microcrystalline cellulose CELLETS^® pellets using hydroalcoholic solution and alcoholic suspension layering techniques to achieve a minimum drug load of 4 mg DM/g pellets. DM-layered CELLETS were coated by Aquacoat dispersion (ready-made ethylcellulose dispersion) using a coating pan technique as a simple and widely utilized technique in pharmaceutical industry. Controlled-release DM-layered pellets showed a release profile comparable to the controlled-release commercial product Cardura^® XL Tablet. Also, the mechanism of DM release from Aquacoat CELLETS was mathematically modeled and imaged by scanning electron microscopy to elucidate drug release mechanisms from the prepared pellet formulations. Accelerated stability studies of the prepared pellets were performed under stress conditions of 40 °C, and 75 % RH for 3 months. In conclusion, preparation of controlled-release DM-layered CELLETS^® is feasible using a simple and conventional coating pan technology.     

Evaluating tamsulosin hydrochloride-released microparticles prepared using single-step matrix coating

The purpose of the present study was to prepare matrix extended release pellets of diclofenac potassium using low amount of release-modifying agents and, to compare its performance in vivo with coated pellets and matrix tablets. Coated pellets were prepared by extrusion-spheronization, followed by double layer coating using different polymers separately. Matrix pellets with different release rate in vitro were prepared by extrusion-spheronization with different kinds of retarding materials. Bioavailability study of different coated pellets revealed that the drug concentration in plasma of beagle dogs was too low to be detected and, implied that the drug was nearly not released from the preparations before reaching colon due to the appearance of lag time in the dissolution process. The phenomenon indicated that slow-release pellets of diclofenac potassium perhaps should not be developed as double membrane-controlled type. The AUC((0 → 24)) of the immediate release pellets, the two matrix pellets and the reference were 304.4, 87.7, 204.1 and 179.1 μg h/ml, respectively. The C(max) of the formulations mentioned above were 46.3, 13.0, 33.6 and 32.1 μg/ml, respectively. All the matrix formulations, including the reference, exhibited incomplete absorption due to the short small intestine transit time and termination of the drug release in the colon because of its limited solubility. The matrix pellets were bioequivalent with the commercially available tablet (Voltaren(?)) although the drug release in vitro of the former was much faster, while the bioavailability of the matrix pellets with similar in vitro drug release to the reference (Voltaren(?)) was much lower than the latter. The results perhaps was caused by lacking of physical robustness in the waxy tablet formulation, resulted in low wet strength and easily destroyed by the mechanical destructive forces and finally introduced faster drug release rate in vivo. It is apparent that preparations with similar performance in vitro may differ a lot in vivo because of the differences in drug release rate in vivo owing to various wet strengths of excipients contained, especially for sustained release products.