Bioequivalence Comparison of Pediatric Dasatinib Formulations and Elucidation of Absorption Mechanisms Through Integrated PBPK Modeling

SPRYCEL^® (Dasatinib) is a Biopharmaceutical Classification System II weakly basic drug that exhibits strong pH-dependent solubility. Dasatinib is currently presented in 2 drug product formulations as an adult immediate release tablet and a pediatric powder for oral suspension. A bioequivalence study comparing the formulations in adult healthy subjects found that overall exposure (AUC_0-24) from suspension treatments was ～9% to 13% lower, Cmax was similar, and median Tmax from powder for oral suspension was ～30 min earlier. To understand the mechanism contributing to this behavior, a combination of biorelevant dissolution studies and physiologically based pharmacokinetic modeling was used to simulate in vivo performance. In vitro biorelevant dissolution confirmed that the rate and extent of release was similar between tablet and suspension formulations (>90% release within first 15 min). Physiologically based pharmacokinetic parameter sensitivity analysis demonstrated particular sensitivity to dosage form gastric residence time. A 12% higher AUC_0-24 was simulated for tablet dosage forms with 10 to 15 min longer gastric transit relative to solutions or suspensions of small particulates (rapid gastric emptying). The corresponding narrow simulated Cmax range also agreed with observed tablet and suspension bioequivalence data. The unique physicochemical properties, absorption characteristics, and inherent differences in dosage form transit behavior are attributed to influence the dasatinib bioequivalence.     

Sustained-release matrix tablets of metformin hydrochloride in combination with triacetyl-beta-cyclodextrin.

The low bioavailability and short half-life of metformin hydrochloride (MH) make the development of sustained-release forms desirable. However, drug absorption is limited to the upper gastrointestinal (GI) tract, thus requiring suitable delivery systems providing complete release during stomach-to-jejunum transit. This study was undertaken to develop a MH sustained-release formulation in compliance with these requirements. The strategy proposed is based on direct-compressed matrix tablets consisting of a combination of MH with the hydrophobic triacetyl-beta-cyclodextrin (TAbetaCD), dispersed in a polymeric material. Different polymers were tested as excipients, i.e. hydroxypropylmethylcellulose, xanthan gum, chitosan, ethylcellulose, Eudragit L100-55, and Precirol. Compatibility among the formulation components was assessed by DSC analysis. All the tablets were examined for drug release pattern in simulated gastric and jejunal fluids used in sequence to mimic the GI transit. Release studies demonstrated that blends of a hydrophobic swelling polymer (hydroxypropylmethylcellulose or chitosan) with a pH-dependent one (Eudragit L100-55) were more useful than single polymers in controlling drug release. Moreover, the main role played by the MH-TAbetaCD system preparation method (i.e. grinding or spray-drying) in determining the behaviour of the final formulation was evidenced. In fact, for a given matrix-tablet composition, different sustained-release effects were obtained by varying the relative amounts of MH-TAbetaCD as ground or spray-dried product. In particular, the 1:1 (w/w) blend of such systems, dispersed in a Eudragit-chitosan polymeric matrix, fully achieved the prefixed goal, giving about 30% released drug after 2h at gastric pH, and overcoming 90% released drug within the subsequent 3h in jejunal fluid.     

A Biopredictive In Vitro Comparison of Oral Locally Acting Mesalazine Formulations by a Novel Dissolution Model for Assessing Intraluminal Drug Release in Individual Subjects

Drug release and availability at the site of action are the major factors determining the clinical response for locally-acting gastrointestinal (GI) drug products. The present work focused on the prediction of site and extent of in vivo mesalazine release after oral administration to a variety of subjects using individualized in vitro drug release experiments. First, experiments mimicking GI passages in average adult subjects were performed. Then, results from a study screening fasted in vivo pH and transit profiles in individual subjects were translated into a novel in vitro dissolution model enabling to mimic individual GI pH-profiles and transit times with physiologically relevant dissolution media. A selection of monolithic and multiparticulate mesalazine formulations with pH-dependent and pH-independent drug release was screened with the novel dissolution model. Results of the study indicate that dosage form performance can be significantly different in individual subjects and highlight the importance of addressing individual physiological parameters relevant to intraluminal drug release when the aim is to predict the in vivo performance of locally-acting mesalazine formulations in individual patients. The novel in vitro dissolution approach thus represents a valuable tool for both improving individual oral therapy with locally-acting GI drug products and assessing bioequivalence of these formulations.     

The disposition of feprazone and its hydroxylated metabolite in human volunteers

1. ¹⁴C-Feprazone administered as a single oral dose (17 mg/subject) to each of 3 human volunteers on the 6th day of repeated dosage with unlabelled feprazone (200 mg/subject, twice daily) was excreted slowly, with only 19-38% of the dose excreted in the urine in 8 days, with a further 27-49% of the dose in the faeces.

2. ¹⁴C-Feprazone had a half-life of 30-33 h, similar to that after single dosage of unlabelled feprazone (22-33 h). The half-life for total ¹⁴C was not significantly different from that for unchanged feprazone, indicating that no metabolite with a very long half-life was formed.

3. Only feprazone and 4′-hydroxyfeprazone were detected in the plasma of subjects dosed orally with feprazone, the metabolite being characterized by mass spectrometry. The time of peak plasma concentration of feprazone was 4-5 h after dosage, and of 4′-hydroxyfeprazone was approx. 25 h. The urine contained feprazone plus its C-glucuronide, and 4′-hydroxyfeprazone plus its conjugate (glucuronide), in the ratio of approx. 5:1.

4. When 4′-hydroxyfeprazone was administered as a single oral dose to a human volunteer the plasma elimination half-life of the metabolite was 18 h, but after administration of feprazone the half-life of 4′-hydroxyfeprazone was 45 ± 29h (10 subjects), indicating the slow hydroxylation of feprazone and the slow excretion of 4′-hydroxyfeprazone. The clearance of feprazone was 5˙2 and of 4′-hydroxyfeprazone was 5˙5 ml/kg h.

5. These studies have shown that even though enterohepatic recirculation of the drug in man is indicated, the plasma half-life of feprazone is unchanged on repeated dosage, and accumulation of the drug at a daily dosage of 2 × 200 mg, does not occur.     

Preparation and in vitro evaluation of pyridostigmine bromide microparticles

Pyridostigmine bromide (PB) is an anticholinesterase agent whose aqueous solubility is high and which has a short elimination half-life. Its dosage rate in the treatment of myastenia gravis is frequent due to the short half-life and it exhibits side effects. Microparticles designed to deliver a pharmaceutical active ingredient efficiently at the minimum dose and also to enhance stability, reduce side effects and modify drug release were prepared in this study using an acrylic polymer (Eudragit) as the vehicle by the spray-drying technique. The drug was either dissolved or dispersed in the polymeric solution and following the preparation of microparticles using different ratios of ingredients, characterization studies including the determination of shape, particle size distribution, amount loaded, release and stability of PB were performed. The results obtained were compared to those of pure PB. Drug release from microparticles could be modified and was found to depend on the shapes of the microparticles. In vitro evaluation results indicate that the frequent dosage and side effects of pure PB may be reduced with the formulation of microparticles.     

Phosphomycin levels in serum and interstitial tissue fluid in a multiple dosage regimen in rabbits

The evolution of phosphomycin (Fosfocina), levels in serum and experimentally induced interstitial tissue fluid and the access of the drug to different organs were studied in rabbits after the administration of a single dose of 60 mg/kg and during a multiple dosage regimen of 60 mg/kg/6 h over three days. Following the administration of a single dose a Cmax value of phosphomycin in interstitial tissue fluid of 80.4 micrograms/ml was reached at 1.2 h. The elimination half-life of the drug from the systemic circulation after a single dose had a value of 1.6 h, and was not significantly different from the value found for the same parameter in the multiple dosage regimen. The disappearance half-life of phosphomycin from interstitial tissue fluid, with a value of 1.9 h for the single dose schedule, was not significantly different from the value of the disappearance half-life of the drug from interstitial tissue fluid in the multiple dosage regimen. Finally, the results of the present study confirm the linearity of phosphomycin kinetics, at least in the conditions studied, and show that the drug is not accumulated in the organs considered.     

A biorelevant dissolution stress test device – background and experiences

Importance of the field: The prediction of the in vivo drug release characteristics of modified release (MR) oral dosage forms by in vitro dissolution tests is a prerequisite for successful product development.

Areas covered in this review: To improve the predictive power of dissolution testing, the authors recently developed a new dissolution test apparatus that simulates physical conditions of the gastrointestinal (GI) passage of MR dosage forms. The simulation includes pressure force exerted by GI motility, shear stress force generated during phases of GI transport and intermittent contact with intestinal fluids while the dosage form is located in an intestinal air pocket.

What the reader will gain: The article briefly describes selected aspects of GI tract physiology, evolution and goals of dissolution testing as well as the development and use of test devices that are intended to simulate GI tract conditions. The data are discussed in the light of the test results obtained with the new dissolution stress test device developed by the authors' group. Achievements reported from 1986 to 2010 are referred to.

Take home message: The new apparatus was evaluated using extended release (ER) tablets of nifedipine and diclofenac. The dissolution characteristics of some of the tested products were strongly dependent on the test conditions and could be distinctly influenced by the mechanical stress events of biorelevant intensity. Results of these experiments thus indicated that a high sensitivity of dosage forms to GI-specific physical conditions has to be regarded as a major cause of irregularities in the drug release profiles, which may result in fluctuations of the individual drug plasma concentration profiles, as, for example, caused by dose dumping.     

Measurement of Drug Concentration in the Stomach After Intragastric Administration of Drug Solution to Healthy Volunteers: Analysis of Intragastric Fluid Dynamics and Drug Absorption

Purpose

To evaluate the time-profile of intragastric fluid volume in humans after intragastric administration of drug solution.

Methods

Eight healthy volunteers were intragastrically administered 150 mL of drug solution containing atenolol (non-absorbable marker) and salicylic acid, then, aliquots of gastric fluid (ca. 2 mL) were sampled for 2 h through the catheter. Rate constants for secretion and emptying of the fluid were obtained by fitting the time-course of atenolol concentration to the simple gastric fluid transit model. Absorption of salicylic acid from the stomach was estimated by comparing its gastric concentration with that of atenolol.

Results

Kinetic analysis of atenolol concentration in the stomach indicated a rapid emptying of the fluid with an average half-life of 4.2 min. Steady-state intragastric fluid volume in 8 volunteers was estimated as 4–133 mL with an average of 42 mL. Intragastric concentration (normalized by dose) of salicylic acid was always lower than that of atenolol, showing approximately 40% of salicylic acid was absorbed from the stomach before emptying to the intestine.

Conclusions

This study provided valuable information on intragastric fluid dynamics and gastric drug absorption in humans to establish a better in vitro-in vivo correlation in oral drug absorption.     

Evaluation of Pulsincap to provide regional delivery of dofetilide to the human GI tract

Pulsincap formulations designed to deliver a dose of drug following a 5-h delay were prepared to evaluate the capability of the formulation to deliver dofetilide to the lower gastrointestinal (GI) tract. By the expected 5-h release time, the preparations were well dispersed throughout the GI tract, from stomach to colon. Plasma analysis permitted drug absorption to be determined as a function of GI tract site of release. Dofetilide is a well-absorbed drug, but showed a reduction in observed bioavailability when delivered from the Pulsincap formulations, particularly at more distal GI tract sites. Dispersion of the drug from the soluble excipient used in this prototype formulation relies on a passive diffusion mechanism and the relevance of this factor to the reduced extent and consistency of absorption from the colon is discussed. In these studies the effects of the degree of dispersion versus the site of dispersion could not be ascertained; nevertheless the scintigraphic analysis demonstrated good in vitro-in vivo correlation for time of release from Pulsincap preparations. The combination of scintigraphic and pharmacokinetic analysis permits identification of the site of drug release from the dosage form and pharmacokinetic parameters to be studied in man in a non-invasive manner.     

The disposition of feprazone and its hydroxylated metabolite in human volunteers

1. 14C-Feprazone administered as a single oral dose (17 mg/subject) to each of 3 human volunteers on the 6th day of repeated dosage with unlabelled feprazone (200 mg/subject, twice daily) was excreted slowly, with only 19-38% of the dose excreted in the urine in 8 days, with a further 27-49% of the dose in the faeces. 2. 14C-Feprazone had a half-life of 30-33 h, similar to that after single dosage of unlabelled feprazone (22-33 h). The half-life for total 14C was not significantly different from that for unchanged feprazone, indicating that no metabolite with a very long half-life was formed. 3. Only feprazone and 4'-hydroxyfeprazone were detected in the plasma of subjects dosed orally with feprazone, the metabolite being characterized by mass spectrometry. The time of peak plasma concentration of feprazone was 4-5 h after dosage, and of 4'-hydroxyfeprazone was approx. 25 h. The urine contained feprazone plus its C-glucuronide, and 4'-hydroxyfeprazone plus its conjugate (glucuronide), in the ratio of approx. 5:1. 4. When 4'-hydroxyfeprazone was administered as a single oral dose to a human volunteer the plasma elimination half-life of the metabolite was 18 h, but after administration of feprazone the half-life of 4'-hydroxyfeprazone was 45 +/- 29 h (10 subjects), indicating the slow hydroxylation of feprazone and the slow excretion of 4'-hydroxyfeprazone. The clearance of feprazone was 5.2 and of 4'-hydroxyfeprazone was 5.5 ml/kg/h. 5. These studies have shown that even though enterohepatic recirculation of the drug in man is indicated, the plasma half-life of feprazone is unchanged on repeated dosage, and accumulation of the drug at a daily dosage of 2 x 200 mg, does not occur.     

Formulation and in vitro evaluation of rifampicin loaded porous microspheres

Rifampicin (RIF) is a major component in fixed dose combination therapy for the treatment of tuberculosis. RIF has low solubility and high permeability with high dose and hence it is classified as class II drug in Biopharmaceutical Classification System (BCS). RIF has poor and variable bioavailability because of its poor solubility, acid decomposition and, drug and food interaction. The present investigation was aimed to develop RIF loaded porous microspheres as a controlled release dosage form. Eudragit based porous microspheres of RIF were prepared by emulsion solvent diffusion method. Prepared porous microspheres were evaluated for its entrapment efficacy, morphology, thermal behavior, crystalline nature, in-vitro drug release and stability in simulated gastric fluid. The entrapment efficacy of drug loaded microspheres was found to be in the range of 19.04a74.57%. Surface morphology revealed the porous and spherical structure of microspheres. Differential scanning calorimetric studies confirmed that formulation process altered the crystalline nature of RIF. In vitro drug release studies indicated that drug to polymer ratio of 2:1 showed more than 85% drug release over the period of 3 h. Stability studies in simulated gastric fluid (SGF) indicated that low relative decomposition of 18.5% was achieved with high drug to low polymer ratio of 1:4. The results obtained from the present investigation concluded that RIF loaded porous microspheres are suitable for developing oral controlled release dosage form of RIF that can prevent acid decomposition and provide better biopharmaceutical properties. Further more the microspheres can be evaluated for preventing the interaction with isoniazid, other drugs and foodstuffs.     

Investigation of human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble/highly permeable drug (efavirenz)

Human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble, highly permeable, micronized drug (efavirenz) was investigated. The tablets and capsule, prepared with samarium oxide and neutron activated to produce radioactive samarium-153, were evaluated for their in vivo disintegration and gastrointestinal (GI) transit in healthy subjects under fasted condition. Scintigraphic images were acquired to coincide with blood sampling times to assess the plasma concentration-time profile in relation to in vivo disintegration and GI transit. The mean gastric emptying times were approximately the same for all three formulations. Although in vivo dosage form disintegration was faster for Tablet A as compared to Tablet B and was similar between Tablet A and the capsule, Tablet A showed a slower rate and extent of drug absorption than Tablet B and the capsule. The results of this study eliminated the initial hypothesis that the difference in in vivo performance between the two tablet formulations is due to a different rate of in vivo disintegration and suggest that for this drug the in vivo dissolution rate of the drug from its disintegrated dosage form was a more important factor affecting the rate and extent of drug absorption.     

In vivo performance of time-controlled explosion system (TES) in GI physiology regulated dogs

In vivo oral absorption study of time-controlled explosion system (TES), using gastrointestinal (GI) physiology regulated dogs, was carried out to predict the feasibility in humans. TES is characterized by rapid drug release with a pre-programmed lag time, which can provide a programmed release system synchronized with circadian rhythm (e.g. asthma attack in the morning), a colon targeting system and a sustained release system with different lag times. In this study, TES containing diclofenac sodium with different lag times of 3 and 6 h (TES-3h and TES-6h) were prepared. TES-3h exhibited good performance in all six GI physiology regulated dogs without remarkable reduction of AUC. In the case of TES-6h, drug absorption was observed ∼6 h after administration in four of six dogs, but plasma level was low. Further, the location of the dosage forms after oral administration was estimated from the gastric emptying time (GET) and the small intestinal transit time (SITT) using a double marker method. As a result, in vivo performance of TES correlated with the intestinal location. It was concluded that TES-3h would perform well in humans and that the environmental water content in the GI tract affected the in vivo dissolution profile of TES when the drug release was initiated after entering the colon.     

The single-point method of dosage prediction: Pharmacokinetic basis and method optimization

Based on the principle of superposition an expression has been established relating a drug concentration at steady-state to a concentration after a single dose. This relationship applies for drugs with linear pharmacokinetics given at equal dosage intervals and it is independent of the route of administration. The relationship provides theoretical justification for the single-point method of dosage prediction reported in the literature. The test conditions in the method can therefore be optimized and the limits of the method defined. The expression can also be used for individualized prediction of maintenance dose after estimation of drug half-life in the patient with no limit to half-life values to which it can be applied.     

Pharmacokinetics of an immediate release, a controlled release and a two pulse dosage form in dogs.

Clinical studies have shown that circadian patterns influence the pharmacokinetics of certain drugs used in the treatment of different diseases. For such drugs, the bioavailability is influenced by the time of administration. The objective of this study was to investigate differences in the pharmacokinetic patterns between a pulsatile drug delivery system using a pulsatile capsule, an immediate release tablet and a controlled release tablet. Metoprolol was chosen as a model drug because of its high solubility and high permeability pattern throughout the GI tract. The dosage forms were administered to four dogs and the plasma levels were measured using LC-MS/MS. Pharmacokinetic parameters were determined for each dosage form. Fluctuations in the plasma time curves over the observation period indicated that physiological factors like motility have an influence on the drug absorption. The comparison of the plasma time curves of the dosage forms showed that each dosage form caused significant differences in the drug plasma levels. The pulsatile drug delivery capsule caused two defined C(max) values for each dose between 1-1.75 and 2.5-3.5h. Implications for the use of a pulsatile drug delivery device for chronopharmacotherapy are discussed. Pulsatile drug delivery offers a promising way for chronopharmacotherapy if the time of administration and pulse time are adjusted to the circadian pattern.     

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.     

The pharmacokinetic modelling of GI198745 (dutasteride), a compound with parallel linear and nonlinear elimination

AIMS: To characterize the pharmacokinetics of the dual 5alpha-reductase inhibitor GI198745 (dutasteride) to allow for more accurate predictions of GI198745 concentrations after different dosing schedules. METHODS: In this randomized, single-blind, parallel group study, 32 healthy male volunteers received single oral doses of GI198745 ranging from 0.01 to 40 mg. Data were analysed by nonlinear mixed effects modelling using NONMEM where both linear and nonlinear pharmacokinetic models were examined. RESULTS: The time course of GI198745 serum concentrations indicated concentration dependent elimination, with the apparent half-life increasing with dose. Data were best described by a two-compartment model with first order absorption and parallel linear and nonlinear elimination pathways. Drug absorption was rapid, and was followed by a short distribution phase. A high volume of distribution (511 l) and a low linear clearance (0.58 l h(-1)) combined to give a half-life of up to 5 (1-7) weeks at high concentrations. As concentrations declined towards Km (0.96 ng ml(-1)), the proportion eliminated by the relatively rapid saturable elimination pathway, with a maximum clearance of 6.2 l h(-1), increased and the half-life reduced to about 3 days. The estimated inter individual variability for the linear clearance was high (CV = 70%). CONCLUSIONS: G1198745 pharmacokinetics are well described by a pharmacokinetic model with parallel linear and nonlinear elimination. Simulations using this model show that at daily doses of 0.1 mg the steady state drug concentrations, and the rate at which these are achieved, are mainly influenced by the nonlinear pathway, while at daily doses above 1 mg they are almost entirely influenced by the linear pathway.     

Formulation and pharmacokinetic evaluation of once-daily sustained-released system of nifedipine with solid dispersion and coating techniques

A novel sustained-release system was developed for poorly water-soluble drugs by applying solid dispersion (SD) technique to improve the solubility. The SD systems composed of polyvinyl pyrrolidone and stearic acid could not control the release of nifedipine. When the above SD granules were coated with ethylcellolulose (EC10, 45 and 100cp), the dissolution rate extended from 16 to 20 h. When the concentration of EC100cp was increased to 4–6 %, the sustained-release formulation F7 and F8 prepared with 4 % EC100cp and 6 % EC100cp, respectively, could control the drug release in a better manner, namely, they could control drug release in the initial hours with a high cumulative amount of drug at 24 h. The mechanism of drug release from F7 and F8 was diffusion coupled with erosion. When immediate-release capsules was orally administered to rabbits, its absorption was very rapid with a short elimination half-life, while a prolonged maintenance of the plasma drug level up to 24 h was obtained for F7 and F8. Furthermore, the oral bioavailability of F7 and F8 was significantly improved. The results suggested that this novel sustained-release system would be a promising system to improve the solubility and sustain the absorption of poorly water-soluble drugs.     

Evaluation of gastrointestinal pH and gastric residence time via the Heidelberg radiotelemetry capsule: Pharmaceutical application

The Heidelberg Radiotelemetry Capsule (7 mm diameter x 20 mm length) represents a noninvasive device to monitor gastrointestinal (GI) pH and to evaluate gastric residence time (GRT) in both animals and humans. Due to its large size and indigestible nature, gastric emptying of the Heidelberg capsule occurs during the 5–15 min of Phase III migrating motor complex (MMC), which is responsible for emptying of indigestible debris leftover from a meal, the so-called housekeeper wave of the GI tract. Following initial in vitro accuracy and in vivo reproducibility studies, the Heidelberg capsule was used in young beagle dogs and normal healthy subjects. In the fasting state, gastric pH was comparable in dogs and humans (1.5 ± 0.04 vs. 1.1 ± 0.15, mean ± SEM), where postprandially a more acidic pH was reported in beagle dogs (2.1 ± 0.04 vs. 3.6 ± 0.4). Both duodenal and fasting intestinal pHs were consistently higher in dogs than humans. Although fasting GRT of the Heidelberg capsule was similar between the two species (1.2 ± 0.33 vs. 1.2 ± 0.45 h), high intersubject variability in the GRT estimation was observed in both dogs and humans. The Heidelberg radiotelemetry technique was utilized in several clinical studies to evaluate the influence of physical and physiological parameters which alter the normal GI motility (i.e., food with varying composition and energy density, posture, gender, age, and gastric alkalinization). The results of pH and GRT measurements via the Heidelberg capsule were found to be sensitive and responsive toward factors which alter the GI motility, and therefore, the Heidelberg capsule may be used in the clinical studies as a model for a large, nondisintegrating solid dosage form (i.e., enteric-coated formulations). Subsequently, the Heidelberg capsule was administered together with the enteric-coated aspirin (which is known for high inter- and intra-subject absorption variability) and with a more challenging enteric-coated formulation, diclofenac sodium. The results demonstrated that by reasonable estimation of the GRT, the Heidelberg capsule is capable of explaining and minimizing the traditional absorption variabilities observed with these formulations. In summary, the Heidelberg radiotelemetry device can be used as a noninvasive means of GI pH and transit time. This accurate and reproducible telemetry system mimics the GI transit of a large indigestible solid dosage form and may be used in both animal research and human oral bioavailability/bioequivalency studies. © 1996 Wiley-Liss, Inc.     

Gastric retentive dosage forms: a review

Gastric retentive dosage forms have been investigated to provide controlled release therapy for drugs with reduced absorption in the lower gastrointestinal (GI) tract or for local treatment of diseases of the stomach or upper GI tract. Gastric retentive dosage forms rely on either natural GI physiology, such as floating or large tablets that depend on delayed emptying from the fed stomach, or those dosage forms that are designed to fight the physiology and avoid emptying in the fasted state through dosage forms of even larger sizes with or without flotation or bioadhesion. To understand the behavior of the dosage forms, an introduction to GI motility and its measurement is provided. Because the fed mode underlies the successful development of dosage forms that rely on size or flotation, the emptying of these dosage forms in the fed mode and identification of the key factors influencing the variability of gastric retention are discussed. The design and limitations of size or density-based fed mode, and mucoadhesive and expandable fasting-state gastric retentive systems are presented.