Forecasting the effect of water gastric emptying patterns on model drug release in an in vitro glass-bead flow-through system.

Oral solid dosage forms are most frequently administered with a glass of water which empties from the stomach relatively fast, but with a certain variability in its emptying kinetics. The purpose of this study was thus to simulate different individual water gastric emptying (GE) patterns in an in vitro glass-bead flow-through dissolution system. Further, the effect of GE on the dissolution of model drugs from immediate-release tablets was assessed by determining the amount of dissolved drug in the samples pumped out of the stomach compartment. Additionally, different HCl solutions were used as dissolution media to assess the effect of the variability of pH of the gastric fluid on the dissolution of three model drugs: paracetamol, diclofenac sodium, and dipyridamole. The difference in fast and slow GE kinetics resulted in different dissolution profiles of paracetamol in all studied media. For diclofenac sodium and dipyridamole tablets, the effect of GE kinetics was well observed only in media, where the solubility was not a limiting factor. Therefore, GE kinetics of co-ingested water influences the drug release from immediate-release tablets, however, in certain cases, other parameters influencing drug dissolution can partly or fully hinder the expression of this effect.

Development Dynamics of Health and Social Infrastructure for the Long-term Care - the Case of the Posavje Region.

BACKGROUND AND PURPOSE: The populations of rural areas across Europe, especially Slovenia, are ageing rapidly and the areas themselves are becoming depopulated. Therefore, this study aims to contribute to our understanding of the population dynamics and provide a method for forecasting housing and other long-term care needs. METHOD: The surveys questioned those responsible for long-term care, the caretakers in institutional care, and current and potential homecare users in rural areas of Slovenia. We wanted to discover what they considered as crucial in the process of long-term care deinstitutionalization. Our 2020-2050 projections are based on the surveys conducted across 38 municipalities in the Eastern Slovenian region and an in-depth empirical study in Posavje. The results are embedded in the demographic projections and the multistate transition model of the declining functional capacities to forecast the needed housing facilities and human resources. RESULTS: The results are the time series of required capacities. Around 60% of respondents in Slovenian rural areas believe that even a better organization of homecare would not allow them to stay at home until death due to inadequately built housing and the absence of a continuous presence of caregivers. These findings were included in the projections. Therefore, community care in the network of Smart Silver Villages was proposed. DISCUSSION: Investments are needed to renovate the housing stock of older adults and construct sheltered, assisted living housing and specialized households in the community. Moreover, proper education and training of human resources would increase the output. In addition, financial solutions are advised to develop Smart Silver Villages.

The Influence of Simulated Fasted Gastrointestinal pH Profiles on Diclofenac Sodium Dissolution in a Glass-Bead Flow-Through System.

High inter- and intra-individual variability in the pH of fluids in the human gastrointestinal (GI) tract has been described in the literature. The aim of this study was to assess the influence of physiological variability in fasted pH profiles of media along the GI tract on diclofenac sodium (DF-Na) dissolution from matrix tablets. Four individual in vivo fasted pH profiles were selected from the literature that differed in pH values and transit times from the stomach to the proximal colon. Using a glass-bead device flow-through dissolution system, these pH profiles were simulated in vitro using a specific media sequence and considering simulated intestinal buffer capacities corresponding to in vivo literature data. Dissolution experiments were then performed in the same system with media sequence following individual pH profiles. In dissolution experiments, where influences of simulated gastric emptying time (GET), gastric pH value, small intestinal transit time, and colonic pH were studied; high influence of gastric pH value and GET on DF-Na dissolution was observed. The effect of variability in pH profiles in the range of individual in vivo data on DF-Na dissolution was also clearly observed in experiments, where dissolution studies were performed following three simulated in vivo individual pH profiles. The differences in DF-Na release between three individual pH profiles were substantial; they also reflected in simulated plasma concentration profiles and can be attributed to pH dependent diclofenac solubility.

In vitro-in vivo-in silico approach in biopharmaceutical characterization of ibuprofen IR and SR tablets.

Within the last decades, physiologically based pharmacokinetic models have emerged into a biopharmaceutical toolkit that has been proven useful in understanding how physicochemical, formulation and physiological factors affect oral drug absorption. The purpose of this study was to develop a drug specific physiologically based pharmacokinetic model that will allow mechanistic interpretation of oral absorption from dosage forms exhibiting different in vitro and different in vivo performance (i.e. immediate release and sustained release tablets) and identification of bioperformance dissolution testing. Ibuprofen was chosen to be used for the "proof of concept" considering it is well characterised and the necessary physicochemical, biopharmaceutical and pharmacokinetic properties for model development could be found in the literature. Gastrointestinal simulation technology implemented in Simcyp® was successful in estimating ibuprofen oral absorption. The developed model exhibited good generalisation ability for the dosage forms studied. The obtained results indicate that the model was sensitive to input kinetics represented by the in vitro drug release profiles obtained under various dissolution conditions. According to the obtained results, reciprocating cylinder apparatus with biorepresentative change in media pH might be considered as bioperformance dissolution in the case of the two ibuprofen SR products studied. These results further justify the use of integrated in vitro-in vivo-in silico approach in estimating bioperformance of oral solid dosage forms.

Analysis of factors influencing gastric emptying of pellets in a fed state.

OBJECTIVES: The aim of the present study is to evaluate the influence of factors such as biopharmaceutical properties and study protocol on the emptying of pellets from the human stomach in a fed state. METHODS: A systematic literature search for data on human gastric emptying of pellets from a fed stomach state investigated by γ-scintigraphy was carried out. After selection of comparable data, a joint statistical analysis on the basis of multiple linear regression with 132 individual t50 values (time for 50% of the pellets to be emptied from the stomach) was performed. Parameters such as a second meal administration that can influence t50 values were also examined and included into the interpretation of the results. RESULTS: The results showed that an increase in the caloric value of the meal in the interval between 1200 and 3600 kJ increased the mean t50 value. Pellets with a density of 2.8 g/cm(3) remained in the stomach longer than pellets of usual density with the same caloric value of the meal. Pellets incorporated in a tablet are emptied faster from the stomach than encapsulated pellets. A 45-min delay in the application of pellets after the start of the meal significantly diminished the mean t50 value, compared with application immediately after consuming the meal. CONCLUSION: Thus, in the development of non-disintegrating pellets intended for fed-state application, all of these cited factors should be considered because of their potential influence on the gastric residence time.

Analysis of small intestinal transit and colon arrival times of non-disintegrating tablets administered in the fasted state.

In this study individual data on tablet gastrointestinal transit times (i.e. gastric emptying, small intestinal transit, ileocecal junction residence, and colon arrival times) were obtained from literature in order to present and analyze their distributions and relationships. The influence of the time of food intake after tablet administration in fasted state on gastrointestinal transit times was additionally evaluated. There were 114 measurements from subjects who received the first meal at 4h after tablet administration. Approximately 32% of the tablets arrived into the colon before the meal intake at 4h. An evident increase in the frequency of colon arrival of tablets within 40min after the meal intake at 4h post-dose was observed, where approximately 39% of all tablets arrived into the colon. This is in accordance with findings described in literature where a meal ingested several hours post-dose accelerates tablet transit through the terminal ileum and shortens the transit through the small intestine. The median (min, max) of gastric emptying, small intestinal transit, and colon arrival times in the group where the first meal intake was at 4h post-dose is 35 (0,192), 215 (60,544), and 254 (117,604) minutes, respectively. The dependence of colon arrival times on gastric emptying times was described by the nonparametric regression curve, and compared with the presumed interval of colon arrival times, calculated by summation of observed gastric emptying times and frequently cited small intestinal transit time interval, i.e. 3-4h. For shorter gastric emptying times the trend of colon arrival times was within the presumed interval. At short gastric emptying times many observation points are also within the presumed interval since this interval coincides with short period after meal intake at 4h post-dose. Additionally, in numerous occasions relatively long ileocecal junction residence times were obtained, which may be important information from the point of view of drug absorption. The findings of gastrointestinal transit times are important and should be taken into consideration when predicting the in vivo performance of dosage forms after oral administration.

Influence of the physiological variability of fasted gastric pH and tablet retention time on the variability of in vitro dissolution and simulated plasma profiles.

The aim of the present study was to show that the physiological variability of fasted gastric pH and tablet gastric retention time contributes to the overall variability of simulated plasma profiles of diclofenac. Those two parameters were implemented into dissolution study and plasma profiles were simulated under assumptions that in vitro dissolution well represents that occurring in vivo, and that absorption profiles are identical to dissolution profiles, as diclofenac is a highly permeable drug. Dissolution experiments were performed using USP 2 apparatus and two consecutive dissolution media, namely, an acidic medium of various pH (ranging from 1-3), where tablets were kept for a certain time (10-200 min), and phosphate buffer (pH 6.8). It was shown that the acid pH value and acid retention time of tablets affect in vitro drug release, and consequently also influence the simulated plasma profiles. Lower acid pH resulted in lower plasma peaks at each studied acid retention time. Longer acid retention time caused lower plasma concentrations at lower acid pH values, whereas at pH 3 higher plasma concentrations were noted. Additionally, it was demonstrated that the variability of both parameters represents an important contribution to the overall variability of plasma profiles.

The role of individual gastric emptying of pellets in the prediction of diclofenac in vivo dissolution.

The objective of the present study was to check for the possibility to successfully predict individual in vivo dissolution/absorption profiles resulting from fasted administration of a diclofenac extended release pellet formulation. For this purpose dissolution profiles were generated with different dissolution setups using a set of media reflecting pH-conditions in the different segments of the gastrointestinal tract. Since gastric emptying of pellets seemed to be a critical factor for in vivo drug release, a set of different gastric residence times was screened in in vitro studies. Subsequently, in vitro release profiles were first directly compared with the individual in vivo absorption profiles and in a second step a mathematical model, which had been developed in a previous study, was applied to calculate predicted individual in vivo release profiles based on in vitro release profiles and individual gastric emptying. The comparison of predicted individual in vivo release profiles and individual in vivo absorption profiles showed a high degree of similarity, thus confirming the suitability of a set of different gastric residence times used in in vitro drug release testing. Additionally, obtained results indicated that a substantial part of variability of diclofenac absorption profiles can be explained by the variability of pellet gastric emptying kinetics.

Enhanced therapeutic effect of LK-423 in treating experimentally induced colitis in rats when administered in colon delivery microcapsules.

LK-423 is a phthalimido-desmuramyl-dipeptide derivative with immunomodulating activity. In the present study the therapeutic efficacy of a colon-specific drug delivery system–LK-423 microcapsules–was examined in the 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced ulcerative colitis model in rats. The colon-specific delivery of the drug using microcapsules relies on the combination of pH (outer gastroresistant coating), time (inner retard coating of Eudragit® RS and RL) and enzyme (pectin core) controlled drug release mechanisms. The optimal in vitro dissolution profile for LK-423 delivery to the colon of rats was obtained after coating newly developed LK-423 loaded pectin cores with 20% w/w of retard coating with a Eudragit® RS/RL ratio of 8.5/1.5 and 30% w/w of enteric coating. Orally administered LK-423 microcapsules were therapeutically more beneficial in treating TNBS-induced ulcerative colitis in rats than orally or rectally administered LK-423 in the form of suspension. Clinical activity scores and colon weight to length ratio were insignificantly lower and the macroscopically estimated degree of healing was significantly greater. On the histological level, the administration of LK-423 microcapsules resulted in most physiological regeneration of intestinal mucosa, indicated by regular architecture of all mucosal tissue components, what is probably related to local drug delivery near the site of inflammation achieved using microcapsules. These results demonstrate that LK-23 colon delivery microcapsules enhance the therapeutic efficacy of the drug and therefore appear to be a useful approach for treating various inflammatory diseases in the large intestine.

Gastric emptying of non-disintegrating solid drug delivery systems in fasted state: relevance to drug dissolution.

IMPORTANCE OF THE FIELD: Knowledge of gastric emptying (GE) of solid drug delivery systems (DDS) is meaningful for the development of new DDS as it enables the design of in vitro dissolution experiments with conditions close to those in vivo in order to predict drug plasma concentration profiles with high reliability. AREAS COVERED IN THIS REVIEW: Gastric emptying of non-disintegrating pellets, tablets and mini-tablets in the fasted state is described on the basis of various studies performed in the last 30 years, which have evaluated the emptying process mostly by gamma scintigraphy. Different influences on GE and mathematical models describing GE kinetics of single and multiunit dosage forms are represented. A discussion on the implementation of these data in the development of drug dissolution testing procedures is given. WHAT THE READER WILL GAIN: Readers will gain an insight into the kinetics and mechanisms of GE processes. Some suggestions on the use of the obtained knowledge in biopharmaceutical testing of DDS are also given. TAKE HOME MESSAGE: Gastric emptying of non-disintegrating solid DDS is a very important process, which might influence drug dissolution, bioavailability and the plasma concentration profile. It is reasonable to consider this process in biopharmaceutical testing of these DDS.

Physicochemical and preclinical pharmacokinetic and toxicological evaluation of LK-423--a new phthalimido-desmuramyl-dipeptide derivative with immunomodulating activity.

INTRODUCTION: LK-423 is a new phthalimido-desmuramyl-dipeptide derivative with immunomodulating activity. As optimized delivery to the site of action appears crucial for further preclinical development of LK-423, the aim of this study was to perform a physicochemical and preclinical pharmacokinetic and toxicological evaluation. METHODS: The solubility, partition coefficient, permeability, and stability profile were determined. Pharmacokinetics were evaluated in rats following intravenous and oral application of LK-423, and in dogs after intravenous administration and oral administration of microcapsules, designed for colon-specific delivery of LK-423 based on pH-, time-, and enzyme-controlled release mechanisms. Additionally, the acute and subchronic toxicity was examined. RESULTS AND DISCUSSION: LK-423 is hydrophilic, sparingly to slightly soluble, and poorly permeable. Stability profile in aqueous solution is pH dependent. A pharmacokinetic study following intravenous application to rats and dogs revealed that LK-423 is rapidly eliminated with a short terminal phase half-life, and high plasma clearance, as well as a limited distribution to the peripheral tissue. Oral bioavailability of LK-423 is low, presumably due to low permeability. Debris of insoluble microcapsule coating in feces and obtained plasma concentration profiles confirm that LK-423 microcapsules are a promising approach for local treatment of inflammatory diseases of the large intestine. Acute and a subchronic toxicity results indicate that LK-423 is a safe and nontoxic drug under the applied experimental conditions.

Antioxidant levels in the pig urinary bladder: distribution within the bladder wall and in the urothelium derived from different bladder regions.

This study was designed to determine the antioxidant levels in the urinary bladder wall layers as well as urothelium derived from different bladder regions. Samples of the urothelium, lamina propria, muscularis, and serosa were prepared from the pig's urinary bladder body, while samples used for regional mapping of the urothelium were prepared from trigone, ventral and dorsal middle bladder body, and apex region. Activities of superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase were determined. Concentrations of ascorbic acid and glutathione were also measured. Antioxidant activities, i.e. concentrations of superoxide dismutase, glutathione peroxidase, glutathione reductase and glutathione, were shown to be highest in the urothelium and progressively lower towards the serosa. Regional mapping of the urothelium singled out apex as the region with the lowest antioxidant activities, i.e. concentrations of glutathione peroxidase, ascorbic acid, and glutathione. The fact that antioxidants are concentrated in the urothelium implies that urothelium functions as a barrier against reactive species. The urothelium derived from the apex is the region with the lowest antioxidant levels and is therefore probably the region most liable to development of oxidative damage.

Gastric emptying of pellets under fasting conditions: a mathematical model.

PURPOSE: To develop a mathematical model that would adequately describe human gastric emptying of pellets under fasting conditions of healthy subjects. METHODS: Scintigraphic profiles representing the gastric emptying of pellets were obtained from the literature. Altogether 19 individual and three mean scintigraphic profiles were collected. Three mathematical models namely; the lag-time exponential (two parameters), the Weibull (two parameters), and the double Weibull (five parameters) model were proposed and fitted to the gastric emptying profiles. RESULTS: Different patterns of gastric emptying (immediate and rapid, delayed but rapid, delayed and slow, and interruptive emptying) were observed, with the emptying time varied from approximately 15 min to more than 3 h. The best model for fitting to the individual profiles was the double Weibull model. This model also provided an insight into the mechanism of interruptive emptying of pellets, observed for some patients. In addition, mean gastric emptying of pellets was calculated using the Weibull model. CONCLUSIONS: Mean gastric emptying of pellets was adequately described by the Weibull model (eta = 61.9 min, beta = 0.895), which could be applied in the design of in vitro dissolution experiments for pellet formulations with pH dependent dissolution.

Effects of UGT1A1*28 polymorphism on raloxifene pharmacokinetics and pharmacodynamics.

AIMS: Raloxifene concentrations were reported to correlate approximately with serum bilirubin levels. Bilirubin is a typical UGT1A1 substrate. Based on these facts, we postulated a hypothesis that UGT1A1 is the key enzyme for metabolic clearance of raloxifene and that the common UGT1A1*28 polymorphism significantly contributes to the large pharmacokinetic variability of raloxifene. METHODS: Serum samples from postmenopausal osteoporotic patients treated with raloxifene were assayed for the concentrations of raloxifene and its glucuronides by liquid chromatography-mass spectrometry-mass spectrometry. The same samples were also genotyped for the presence of UGT1A1*28 polymorphism by the single-strand conformation polymorphism method. The pharmacodynamic effect was evaluated by measuring the change in bone mineral density (BMD) in femoral neck, hip and lumbar spine after 12 months' raloxifene therapy. RESULTS: Patients homozygous for the *28 allele showed significantly, twofold higher raloxifene glucuronide concentrations compared with the hetero- and homozygotes for the wild-type allele: 558 +/- 115 nmol l(-1) compared with 295 +/- 43 nmol l(-1), respectively (P = 0.012). This indicates a higher raloxifene exposure in the *28/*28 group. Consequently, a significantly greater increase in hip BMD was observed in subjects homozygous for the *28 allele compared with the group carrying at least one copy of the wild-type allele: 4.4 +/- 2.4% compared with 0.3 +/- 1.4% (P = 0.035). CONCLUSIONS: In this study it is shown that a relatively common UGT1A1*28 polymorphism may considerably influence raloxifene pharmacokinetics and pharmacodynamics. Underlying mechanisms and clinical implications of our findings are also discussed.

Rapid differentiation of superficial urothelial cells after chitosan-induced desquamation.

Superficial cell desquamation followed by differentiation of newly exposed superficial cells induces regeneration of the urinary bladder epithelium, urothelium. In the present work, chitosan was evaluated as a new inducer of urothelial cell desquamation, in order to study the regeneration of mouse urothelial cells in vivo. Intravesical application of chitosan dispersion caused complete removal of only the superficial layer of cells within 20 min of treatment. Differentiation of the new superficial layer was followed by the appearance and distribution of three urothelial differentiation markers, tight junction protein ZO1, cytokeratin 20 and the maturation of the apical plasma membrane. The arrangement of ZO1 into continuous lines in individual cells of the intermediate layer was already found after 10 min of chitosan application, when desquamation had just started. The appearance of the apical membrane changed from microvillar to typically scalloped within 20 min of regeneration, while complete arrangement of the cytokeratin 20 network took 60 min. These findings provide a new perspective on the rate of the differentiation process in the urothelium and make chitosan a new and a very controllable tool for studies on urothelial regeneration.

Shape optimization and characterization of polysaccharide beads prepared by ionotropic gelation.

The shape of drug loaded polysaccharide beads produced by ionotropic gelation has been optimized, with the aim of producing spherical beads suitable for further technological operations, such as coating. The optimization was performed on a model system sodium alginate/theophylline by inclusion of various fillers. Incorporation of excipients markedly influenced the morphological characteristics of the beads. The undesired irregular shape of beads caused by incorporation of the drug could only be improved by incorporating a combination of polycarbophil (PK) and polyvinylpyrrolidone (PVP). The spherical shape of these beads was stabilized mechanically by numerous air bubbles trapped inside the beads, which prevented the collapse of the beads during drying. The optimized method was shown to be applicable to a target system of pectin and an anti-inflammatory drug, LK-423.

Heparin decreases permeability of pig urinary bladder wall preliminarily enhanced by chitosan.

Chitosan significantly increases the permeability of the isolated pig urinary bladder wall by causing urothelial desquamation, the extent of which depends also on the concentration of the polymer. By desquamation permeability barriers of the urothelium are removed. To gain additional insight into the mechanism by which chitosan acts an absorption enhancer into urinary bladder mucosa, we evaluated the influence of a polysaccharide heparin on the permeability of isolated pig urinary bladder wall preliminarily treated with chitosan. Moreover, we aimed to establish whether the effect of heparin depends on its concentration and on the degree of urothelial desquamation caused by chitosan. In the permeability studies performed by the use of diffusion cells, transport of a model drug, pipemidic acid, into the isolated pig urinary bladder wall was determined. Heparin did not have a significant effect on the permeability of the intact urothelium. When applied to the urinary bladder wall, whose permeability was preliminarily enhanced by 0.005% or 0.001% w/v chitosan, heparin decreased the permeation of pipemidic acid into the bladder wall to a level not significantly different from the intact tissue. However, the effect of heparin was not significant at the highest concentration of chitosan tested, where the damage to the urothelium was much more intense compared with that found at lower concentrations of the polymer. The formation of complexes between pipemidic acid and heparin cannot be excluded completely, but it seems that they are not the main reason for the decreased permeation of pipemidic acid in the presence of heparin. By application on the urothelium, damaged by chitosan, heparin is supposed to form a layer on the surface of the urothelium that prevents the transport of the model drug into the bladder wall. In this way heparin probably restores the impermeability properties of the urinary bladder wall to a degree dependent on the urothelial damage.

Development and validation of a liquid chromatography-tandem mass spectrometry assay for determination of raloxifene and its metabolites in human plasma.

This paper describes the development and validation of a method for the detection of raloxifene (Ral) and its two glucuronide metabolites, raloxifene-6-glucuronide (M1) and raloxifene-4'-glucuronide (M2), in human plasma samples. Both glucuronides were synthesized enzymatically, purified and used as authentic standards. The assay involves a simple solid phase extraction (SPE) procedure of 0.5 mL of human plasma and subsequent analysis by LC-MS-MS. The recoveries were higher than 71% and chromatographic separation of all the analytes was accomplished in less than 7 min. Linear ranges (r(2)>0.99) were found from 0.200 to 340 microg/L, from 1.600 to 2720 microg/L and from 0.088 to 60.00 microg/L, for M1, M2 and Ral, respectively. The limits of detection achieved were 8, 11 and 6 ng/L for M1, M2 and Ral, respectively. The method presented was successfully applied to a genetic polymorphism study of 47 plasma samples from women taking Evista (raloxifene hydrochloride).

Permeability of pig urinary bladder wall: time and concentration dependent effect of chitosan.

Chitosan in 0.5% w/v concentration enhanced the permeability of the isolated pig urinary bladder wall by desquamation of the urothelium as ascertained in our previous study. The aim of the present work was to determine the time and concentration dependence of chitosan's effect on the permeation of a model drug into the bladder wall and to establish if the mechanism of permeation enhancement depends on the concentration of chitosan used. In the permeability studies performed by the use of diffusion cells, transport of a model drug moxifloxacin into the isolated pig urinary bladder wall was determined. For morphological observations of the urothelium in response to chitosan treatment scanning and transmission electron microscopy were applied. Within 90 min the effect of chitosan on the tissue amounts of moxifloxacin gradually increased and approached its plateau. In one hour even 0.0005% w/v dispersion of chitosan significantly enhanced the permeability of the pig urinary bladder wall for the model drug and at 0.001% w/v concentration the maximal effect on the tissue permeability was achieved. All concentrations of chitosan that significantly enhanced the permeability of the bladder wall triggered necrosis of superficial cells or desquamation of the urothelium. However, at lower concentrations and shorter exposure times the damage of the urothelium was limited to the changes in tight junctions. Chitosan was ascertained to increase the permeation of moxifloxacin into the urinary bladder wall in a time and concentration dependent manner.

HPLC analysis of raloxifene hydrochloride and its application to drug quality control studies.

Raloxifene hydrochloride is a selective estrogen receptor modulator and is currently being used for prevention of osteoporosis in postmenopausal women. In this article, a high performance liquid chromatography (HPLC) method for detection of raloxifene hydrochloride was developed and validated using an ultraviolet (UV) and coulometric detectors. Limit of quantification (LOQ) was 0.336 and 0.610 mg L(-1) for coulometric and ultraviolet detectors, respectively. Acceptable accuracy (93.1-100.3%) as well as intra- and inter-day precision (CV