UGT1A1*28 polymorphism influences glucuronidation of bazedoxifene.

Bazedoxifene is used for the prevention and treatment of osteoporosis. After peroral application, bazedoxifene is metabolized by UDP-glucuronosyltransferases (UGTs) to bazedoxifene-4'-glucuronide (M4) and bazedoxifene-5-glucuronide (M5). It has already been shown that a relatively common UGT1A1*28 polymorphism can considerably affect raloxifene pharmacokinetics and pharmacodynamics. As pharmacokinetics of bazedoxifene and raloxifene are very similar, the influence of UGT1A1*28 polymorphism on metabolism of bazedoxifene was investigated by genotyped microsomes. Our results indicate an influence of UGT1A1*28 allele on the formation clearance of both bazedoxifene metabolites. The decreased metabolic clearance was most pronounced in microsomes from polymorphic homozygote (*28/*28) where a 7 to 10-fold lower metabolic clearance was observed for both metabolites compared to other genotypes. In conclusion, the significant UGT1A1*28 genotype effect on bazedoxifene intrinsic metabolic clearance indicates that this subject is worth further exploration in vivo and provides valuable information research in this field.

Prediction of the in vivo performance of enteric coated pellets in the fasted state under selected biorelevant dissolution conditions.

The purpose of this research was to predict the in vivo dissolution of lansoprazole from enteric coated pellets in the fasted state using a biorelevant flow-through dissolution method with low flow rates and volumes close to those in vivo. Additionally, a novel rotating stirring element, composed from magnet inserted in a silicone tube, was used to produce the movement of the pellets and expose them to slightly increased physical stress. Obtained dissolution results were compared to the dissolution results of our previous work using the USP IV with higher flow rate (11 ml/min). As drug release from enteric coated pellets usually starts in the small intestine, the influence of pellets' residence time in the gastric medium and additionally the effect of different media on drug release was studied. Prolongation of residence time in an acidic medium had only minor effect on the release rate after initial lag time, but significantly reduced the total amount of the drug released from both tested formulations, which was attributed to the drug's degradation in an acidic medium. The increased physical load on the pellets induced by the rotating stirring element compensated for the decrease of flow rate from 11 ml/min using the USP IV to 3 ml/min using the non-compendial system. Considering also gastric emptying kinetics good prediction of the in vivo release was achieved compared to in vivo absorption data obtained from a pharmacokinetic study under fasting conditions. Thus, using more physiologically relevant dissolution conditions, expressed through low volume and lower flow rate, and in combination with increased mechanical stress we obtained equally good in vitro/in vivo correlation as using USP IV and higher flow rates. Comparison of the dissolution results obtained with two different systems provided additional insight into product behaviour and improved prediction of in vivo performance.

The influence of gastric emptying kinetics on the drug release from enteric coated pellets in fasted state: an in vitro/in vivo correlation.

The absorption and bioavailability of drugs can be substantially affected by the transit of dosage forms through the gastrointestinal (GI) tract. Gastric emptying is one of the most critical parameters contributing to this inter- and intra-individual GI transit variability. It is especially important for the delayed release dosage forms whose release depends on the local environment and begins when the dosage form passes pylorus and comes into contact with higher pH medium in small intestine. The purpose of our research work was to predict the in vivo dissolution from enteric coated pellets for population and establish a good in vitro/in vivo correlation (IVIVC) with mean in vivo absorption profiles, obtained in a pharmacokinetic study under fasting conditions. The dissolution tests were carried out on a USP 4 - flow-through cell with enteric coated pellets containing an acid-labile drug and formulated as orodispersible tablets. Using several residence times in an acidic medium, we simulated the gastric emptying of the pellets and the exposure of different fractions of the pellets to the gastric medium for different periods of time. The amount of drug released decreased with the increasing time of exposure to the acidic medium due to the drug's degradation. The mean in vivo dissolution profiles, which were predicted on the basis of experimentally determined dissolution profiles and mathematical model of pellets' gastric emptying, gave a very good IVIVC with the mean in vivo absorption profiles.

Mucoadhesion on urinary bladder mucosa: the influence of sodium, calcium, and magnesium ions.

The aim of the present work was to establish if different cations present in the lumen of the urinary bladder at the time of application affect the mucoadhesion strength of cationic chitosan, anionic sodium carboxymethyl cellulose (NaCMC), and nonionic hydroxypropyl cellulose (HPC). The mucoadhesion strength of polymeric films was determined on pig urinary bladder mucosa. Sodium, calcium, and magnesium ions decreased the mucoadhesion strength of all three polymers except NaCMC, whose detachment forces were not influenced by the presence of sodium. Lower mucoadhesion strength in the presence of cations should be considered when drug delivery systems, for example microspheres, containing the tested mucoadhesive polymers are applied intravesically. In the majority of the experiments, cations decreased the mucoadhesion strength of the polymers already in concentrations normally present in urine. For stronger mucoadhesion, application of microspheres into the empty urinary bladder would be recommended. Additionally, the mucoadhesion properties of the tested polymers could be controlled by the selection of a proper medium for the suspension of microspheres. Namely, for all three polymers bivalent calcium and magnesium had stronger influence on mucoadhesion compared to univalent sodium, and with increasing concentrations of cations mucoadhesion strength of the polymers decreased.

Enhanced permeability of the urinary bladder wall: the role of polymer charge.

The urothelium is usually impermeable to substances present in the urine. In the current work the possibility of using different absorption enhancers in the development of intravesical drug delivery systems was explored. To establish the role of the polymer charge on its ability to improve bladder wall permeability, cationic poly-L-arginine, anionic NaCMC and alginate as well as nonionic HPC and HPMC were tested. The permeability experiments were performed on isolated pig urinary bladders. We established that the charge of the polymer affects its ability to enhance the permeability of the urinary bladder wall, but to a limited extent. Positively charged polymers were the most promising absorption enhancers for the urinary bladder wall. In order to significantly enhance the permeability of the bladder wall, higher concentrations of poly-L-arginine were needed compared to chitosan. Moreover, chitosan reached the plateau of its absorption enhancement effect after 60 min, while poly-L-arginine increased the permeability continuously over 90 min. In contrast to polycarbophil, two other anionic polymers, NaCMC and alginate, did not significantly enhance the permeation of pipemidic acid into the tissue. Interactions between the polymers and the drug might prevail over the potential effect of NaCMC and alginate on tissue permeability. Furthermore, for the nonionic polymers HPMC and HPC an insignificant influence on bladder wall permeability was determined. Therefore, the selection of absorption enhancers for intravesical drug delivery systems is limited and cannot be done only on the basis of polymer charge.

Cost-effectiveness of antipsychotics for outpatients with chronic schizophrenia.

AIMS: The aim of the present analysis was to evaluate the cost-effectiveness of alternative treatments for outpatients with chronic schizophrenia from the healthcare payer's perspective. METHODS: Decision analysis was used to evaluate the cost-effectiveness of the following antipsychotic drugs: amisulpride, aripiprazole, haloperidol (oral formulation), haloperidol (depot formulation), olanzapine, quetiapine, risperidone (oral formulation), risperidone (depot formulation) and ziprazidone. Clinical and economic outcomes were modelled over 1-year time horizon. Effectiveness was measured as a percentage of patients in remission. Clinical parameters used in the model included compliance rates, rehospitalisation rates for compliant and non-compliant patients, duration and frequency of hospitalisation, and adverse event rates. One-way sensitivity analysis was performed to test the robustness of the model. RESULTS: The most effective treatment was treatment with olanzapine where 64.1% of patients remained in remission. The least effective treatment was treatment with quetiapine where 32.7% of patients remained in remission. Overall costs ranged from 3,726.78 Euro for haloperidol to 8,157.03 Euro for risperidone in depot formulation. Inpatient costs represented the major part of costs for most of antipsychotic drugs. Typical antipsychotic drugs had substantially smaller outpatient costs (6.5%) compared with atypical antipsychotics (37.9%). In the base case scenario the non-dominated treatment strategies were haloperidol, haloperidol decanoate and olanzapine. Additionally, risperidone can also be considered to be part of the efficient frontier based on the sensitivity analysis results. CONCLUSION: Among second-generation antipsychotics, which have a better safety profile than first-generation antipsychotics, olanzapine and risperidone showed to be the most cost-effective treatment strategies for outpatient treatment of chronic schizophrenia.

Kinetic model of drug distribution in the urinary bladder wall following intravesical instillation.

Intravesical administration of cytotoxic agents is commonly used in urological practice for treatment of superficial bladder cancer. The leading motive is optimisation of drug delivery near the site of action and reduction of systemic toxicity. Bladder pharmacokinetics is complicated by several mechanisms. The objectives of this work were to develop a kinetic model of drug distribution in the bladder wall following intravesical instillation and to study the effect of various parameters on tissue and systemic drug exposure and explore the potential benefits of permeability enhancing effects of chitosan (CH) and polycarbophil (PC) through simulation. Key elements of the model are variable urinary drug concentration due to urine formation and voiding, biphasic diffusion in the bladder tissue and systemic absorption. Model parameters were estimated from bladder-tissue concentration profiles obtained in previous in vitro experiments with pipemidic acid (PPA) as a model drug. The results support further investigations on application of CH and PC in intravesical drug delivery. Both polymers increase permeability of the bladder wall by diffusion enhancement in the urothelium and presumably by improving the contact with the bladder surface. The developed mathematical model could serve for optimisation of intravesical drug delivery and future development of intravesical drug delivery systems.

Characterization of calcium alginate beads containing structurally similar drugs.

The aim of this study was to investigate the characteristics of alginate beads prepared by ionotropic gelation in which structurally similar drugs were incorporated. For this purpose theophylline and theobromine were selected as model drugs. The influence of incorporated drugs on bead characteristics such as size, shape, and morphology, as well as encapsulation efficiency, was examined. It was found that theobromine as well as theophylline content in beads significantly decreased with increasing hardening time due to drug diffusion into the hardening media. In theobromine beads the drug content was extremely improved by dropping the alginate and drug solution into an acidic calcium chloride solution, while theophylline content was to some extent improved by the hardening of beads in a calcium chloride solution saturated with the drug. The most evident difference between theophylline and theobromine beads was in their shape and morphology. Theobromine beads were round, while theophylline ones had an irregular shape with an extremely wrinkled surface. The distinction in shape was highly dependent on drug content. Additionally, it was demonstrated that beads' shape was dependent on preparation conditions as well. On the basis of x-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analyses and scanning electron microscope (SEM) photographs it was found that the most of the drug in bead was present in an amorphous state. Therefore, it is suggested that some drug-alginate interactions could be present in beads and might be responsible for the different shape of theophylline and theobromine beads. Thus it can be concluded that the preparation of beads by ionotropic gelation cannot be generalized even though structurally similar drugs are incorporated.

Predicting the anti-hypertensive effect of nitrendipine from plasma concentration profiles using artificial neural networks.

Nitrendipine is an effective and safe calcium-channel blocker for the treatment of mild to moderate hypertension. The aim of this study is to show that an artificial neural network (ANN) model of the relationship between nitrendipine plasma levels and pharmacodynamic effects can be built and used for pressure-drop prediction after oral administration of the drug in spite of the poor correlation between plasma concentrations and the effect. To achieve the goal, the following steps were taken: evaluation of the quality of the database for training the ANN, definition of the optimal input set for the ANN, and prediction of the diastolic pressure drop using the ANN. The possible consequences of successful ANN modelling are an optimisation of the drug administration regimen, to achieve the best possible effect, as well as optimal drug formulation for drugs with complicated pharmacokinetic/pharmacodynamic relationships.

Determination of microsphere solidification time in the solvent evaporation process.

The aim of this work was to define the time of microsphere solidification during the solvent evaporation process. Microspheres were prepared by the solvent evaporation method, using acetone/liquid paraffin solvent system, ketoprofen as a model drug and Eudragit RS as a matrix polymer. Two sets of experiments were performed--in the first one the initial temperature of the emulsion system was 5 degrees C and in the second one 25 degrees C. In each set, two batches of microspheres were compared at constant emulsion stirring rate 250 and 1000 rpm and intermediate batches where the emulsion stirring rate was lowered from 1000 to 250 rpm at pre-defined times after the beginning of the inner phase solvent evaporation. By comparison of the properties of these microspheres, an insight was obtained into the mechanism of microspheres formation. The criterion for determination of microsphere solidification time was the resemblance between the microsphere properties of the batches prepared by stirring rate change and the batch prepared by constant stirring at 1000 rpm. A stirring rate change after the solidification has no influence on microsphere properties, that means that they are the same as of the batch prepared by constant stirring at 1000 rpm. The results of the sieve analysis and particle size distribution of microspheres show that the time of microspheres solidification is in the interval between 15-20 min if the initial temperature is 5 degrees C and between 10-20 min if the initial temperature is 25 degrees C. From the release profiles of ketoprofen, one can infer that the times of solidification for both initial temperatures are a bit lower. The microscopic pictures, which enable one to follow the processes in the system, confirmed the result obtained by the sieve analysis. In spite of its inability to distinguish between single particles and agglomerates, the sieve analysis enabled one to determine the actual time of solidification, while the drug release determination was not sensitive enough to trace small differences in surface area due to particles aggregation.

Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose.

Warfarin is an anticoagulant drug with narrow therapeutic index and high interindividual variability in dose requirement. S-warfarin is metabolized mainly by polymorphic cytochrome P450 (CYP) 2C9. We systematically quantified the influence of CYP2C9 genotype, demographic factors and concomitant drug treatment on warfarin metabolism and maintenance dose. The mean warfarin doses were lower in carriers of one (2.71 mg/day, 59 patients) and two polymorphic alleles (1.64 mg/day, 11 patients) than in carriers of two wild-type alleles (4.88 mg/day, 118 patients). Multiple regression analysis demonstrated that CYP2C9 genotype, age, concomitant treatment with warfarin metabolism inducers and lean body weight contributed significantly to interindividual variability in warfarin dose requirement (adjusted R(2)=0.37). The same factors, except for age, significantly influenced S-warfarin clearance (adjusted R(2)=0.42). These results can serve as a starting point for designing prospective studies in patients in the initiation phase of genotype-based warfarin therapy.

Determination of main low molecular weight antioxidants in urinary bladder wall using HPLC with electrochemical detector.

The aim of the present work was to develop validated HPLC method using electrochemical detector for simultaneous detection of low molecular weight antioxidants (LMWA) in urinary bladder. Furthermore, the method was applied to study the distribution of LMWA in urinary bladder wall. The ascorbic acid (AA), glutathione in reduced (GSH) and oxidized (GSSG) form and uric acid (UA) were resolved by isocratic elution from C18 reversed-phase column. The bladder tissue sample preparation involved extraction with meta-phosphoric acid solution for LMWA stabilization. The AA, GSH and UA tissue peak was identified by different approaches. The obtained method validation parameters were in acceptable range: intra-day precision (<4.4%), intra-day accuracy (<8.4%), inter-day precision (<9.4%) and inter-day accuracy (<15.6%). Additionally, the method provided good linearity (r2>0.99) and recoveries (98.9-112.6%). The distribution of LMWA in urinary bladder was determined by measuring their concentration in bladder wall layers: urothelium, lamina propria, muscularis and serosa. The validated method was able to quantify the reduced form of all three LMWA in all four bladder wall layers. The LMWA concentrations were decreasing from urothelium to serosa except of UA. The developed HPLC method with electrochemical detection of LMWA is simple, fast and can be used for simultaneous quantification of LMWA in tissues, which contain low concentrations of antioxidants.

Use of statins in primary and secondary prevention of coronary heart disease and ischemic stroke. Meta-analysis of randomized trials.

OBJECTIVE: To estimate the relative risk reduction of the clinical outcomes (coronary events, strokes, cardiovascular, non-cardiovascular and all-cause mortality) associated with statin therapy in primary and secondary prevention. DATA SOURCES: A literature search of the Medline and Cohrane databases for articles published from 1985 to July 2002 was performed. The data on systematic reviews and preliminary reports were also included in this study. Primary and secondary prevention trials and regression trials were eligible. DATA EXTRACTION AND STATISTICAL METHOD: Data were extracted by 2 authors according to the defined inclusion criteria. Disagreements were resolved by consensus or by a third reviewer. Testing for heterogeneity was applied and on the basis of these results a fixed effect model or a random effect model was used for calculation of relative risk values (RR) and 95% confidence intervals (95% CI). Sensitivity analysis tested the impact of the individual study--duration of study, type of statin therapy and study size. The number of patients needed to treat was calculated as an absolute measure of clinical effectiveness of statin therapy when appropriate. RESULTS: Data from 15 trials with 63,410 participants and mean duration of treatment of 3.6 years, were included in this overview. Tests for heterogeneity showed that the variability between study estimates is sufficiently small to assume that they are estimating the same underlying treatment effect. Statin therapy was associated with a 22% reduction in total cholesterol, 29% reduction in LDL cholesterol, 12% reduction in triglycerides and 6% increase in HDL cholesterol. Overall (primary and secondary studies) statin therapy significantly reduces relative risk of coronary events (RR, 0.73, 95% CI, 0.68, 0.77, *p < 0.0001), relative risk of cardiovascular disease mortality (RR, 0.78, 95% CI, 0.73, 0.84, *p < 0.0001), relative risk of non-fatal stroke (RR, 0.74, 95% CI, 0.67, 0.82, *p < 0.0001), relative risk of total (fatal and non-fatal) stroke (RR, 0.77, 95% CI, 0.70, 0.84, *p < 0.001) and relative risk of all-cause death (RR, 0.85, 95% CI, 0.81, 0.89, *p < 0.0001). There was a slight and insignificant reduction of relative risk in non-cardiovascular mortality (RR, 0.94, 95% CI, 0.86, 1.03, p = 0.1677) and fatal strokes (RR, 0.86, 95% CI, 0.70, 1.07, p = 0.1912). Sensitivity analysis showed the robustness of our results for all outcomes. The results were not altered if an individual study was removed from meta-analysis. CONCLUSIONS: This overview indicates that statin treatment reduces the relative risk of occurrence of coronary events, cardiovascular disease mortality, non-fatal strokes and all-cause mortality. While secondary prevention with statins provides considerable improvement of cardiovascular morbidity/mortality, primary prevention with statins provides only small and clinically hardly relevant improvement of cardiovascular morbidity/mortality.

Pathways of paracetamol absorption from layered excipient suppositories: artificial intelligence approach.

When studying paracetamol availability after rectal administration, the differences between slower and faster release suppositories were discovered. Approach with modelling and simulation of compartment-based models was used to explore the differences. A study of paracetamol from layered excipient suppositories shows that many different mechanisms are involved in the drug pharmacokinetics. There is also a large number of articles, each dealing with only one or with a few of the mechanisms. However, there is little information available on how the mechanisms interact in the organism and thus govern the pharmacokinetics of the drug, which means that systemic view in the expert knowledge is missing. In the case of paracetamol rectal availability the use of partially fuzzyfied model allowed systemic combination of all described mechanisms found in the literature and measured data. In spite of non-identifiability, the model showed that patterns that explained differences in bioavailabilities of the two formulations of suppositories could be found. Results of modelling and simulation show that "in vivo" there is practically no difference in cumulative release profiles between the two formulations. However, due to higher content of mono-di-glycerides in a slower release formulation, the extent of absorption is augmented both by absorption-enhancing effect of mono-di-glycerides and the liver bypass mechanism via diminished viscosity.

Influence of chitosan and polycarbophil on permeation of a model hydrophilic drug into the urinary bladder wall.

Influence of dispersions of mucoadhesive polymers chitosan and polycarbophil on permeability properties of urinary bladder was investigated in vitro on isolated porcine urinary bladder. Pipemidic acid as a model hydrophilic drug was used. Its distribution in the bladder wall was determined from actual tissue concentrations by a method based on sectioning of frozen tissue and extraction of tissue slices. Pipemidic acid tissue concentration versus tissue depth profiles were evaluated by a diffusion model assuming constant diffusion coefficient. Increase in bladder wall permeability was observed in the presence of both polymers. Apparent permeability (mean+/-S.D.) of urinary bladder wall was increased 2.7+/-2.9 and 2.8+/-2.0 times for chitosan, and 2.3+/-2.0 and 4.3+/-4.2 times for polycarbophil at 0.5 and 1.0%, w/v polymer concentration, respectively. This increase is a consequence of the increased permeability of urothelium. These findings support investigations on application of chitosan and polycarbophil in development of mucoadhesive intravesical drug delivery systems. Experimental model may be applied to evaluate the results of experiments with drugs used in intravesical therapy.

Mucoadhesion on pig vesical mucosa: influence of polycarbophil/calcium interactions.

The influence of polycarbophil/calcium interactions on the mucoadhesive properties of polycarbophil has been examined. Polycarbophil dispersions and films with different concentrations of calcium or sodium ions were prepared and the following parameters were measured: detachment force on pig vesical mucosa, zeta potential, pH and viscosity. Polycarbophil detachment force decreased significantly in the presence of calcium but not sodium. Both ions decrease the pH of polycarbophil dispersions. On the other hand, altering the pH of hydrated polycarbophil films in the absence of added ions had an insignificant effect on detachment force. Both ions reduce the absolute values of polycarbophil zeta potential, calcium more efficiently than sodium. We could conclude that decreased mucoadhesion strength of polycarbophil in the presence of calcium is due to the chelation of polycarbophil carboxylic groups by calcium and crosslinking of polymer. The crosslinked polymer chains would be expected to be less flexible, and therefore, interpenetrate to a lesser extent with the glycosaminoglycans of mucus. Additionally, the interactions between functional groups of polycarbophil and mucus glycosaminoglycans are lowered due to the calcium, blocking the carboxylic groups. The mechanism of calcium influence on viscosity of polycarbophil dispersions appears to be different: repulsion between ionised carboxylic groups of polycarbophil prevails over the crosslinking of polycarbophil by calcium.

The enhancement of pipemidic acid permeation into the pig urinary bladder wall.

The influence of interactions between polycarbophil and calcium on a model drug permeation into the pig urinary bladder wall was investigated. Pipemidic acid was used as a model drug. One percent w/v polycarbophil dispersion significantly increases the permeation of pipemidic acid into the urinary bladder wall. The enhanced absorption of pipemidic acid caused by polycarbophil is significantly less pronounced in polycarbophil dispersions containing calcium. The enhancement of pipemidic acid permeation into the urinary bladder wall could be due to the opening of tight junctions, which causes higher paracellular permeability. In the case of polycarbophil dispersion with calcium some carboxylic groups of polymer are already occupied with calcium, present in the dispersions. As a consequence extracellular calcium binds to polycarbophil in lower extent if compared with polycarbophil dispersion without calcium and transport is increased to a lesser degree. We concluded that the mechanism of drug absorption enhancement caused by polycarbophil could be similar for urinary bladder as described in the literature for intestinal mucosa.

The influence of stirring rate on biopharmaceutical properties of Eudragit RS microspheres.

Eudragit RS microspheres containing pipemidic acid, as a model drug, were prepared by the solvent evaporation method using an acetone/liquid paraffin solvent system. The aim of the work was to evaluate the influence of stirring rate on the average particle size, particle morphology, drug content and release kinetics, as well as the influence of particle size on microsphere morphology, drug content and release kinetics. Stirring rate has been found to significantly influence the average diameter of microspheres. The average diameter decreases as the stirring rate increases. This can be explained by production of a finer dispersion of droplets when higher stirring rates are applied and, consequently, by the formation of smaller microspheres. With increasing stirring rate and increasing fraction particle size the drug content also increases. It is assumed that this dependence is a consequence of an uneven diffusion of the drug from the inner to the outer emulsion phase, and an uneven encapsulation of drug particles during the preparation. Drug release follows the Higuchi model. As seen from SEM photographs, larger microspheres are more porous and the microspheres produced at higher stirring rates are more porous than those produced at lower stirring rates. This explains the unexpected finding that the release rate increases as the fraction particle size and the stirring rate increase.

Antioxidative properties of pig vesical mucosa: a comparison with gastric and intestinal mucosa.

The antioxidative properties of pig urinary bladder mucosa were compared with those of gastric and intestinal mucosa using nitroxide radicals. Electron paramagnetic resonance (EPR) method was used to monitor the metabolic processes of nitroxides in mucosae. The reduction of nitroxides was measured on intact luminal surfaces of gastric, intestinal, and urinary bladder mucosa, as well as in homogenates of mucosa surface layer. Furthermore, N-ethylmaleimide and ascorbate oxidase have been used to characterize the reducing agents in urinary bladder mucosa homogenates. The nitroxide concentration decrease on intact mucosa of the urinary bladder was significantly different from those of the gastric and the intestinal mucosa. The concentration decrease was the largest for intestinal mucosa and the smallest for bladder mucosa. On the other hand, homogenates exhibit the largest nitroxide reduction rates for the bladder mucosa and the smallest for the gastric mucosa. In the bladder surface layer homogenates ascorbate and thiol-containing reducing agents were found and their coupled action in the nitroxide reduction process was established. The mucosa of urinary bladder is protected against nitroxide free radicals by a relatively low permeability and very active endogenous reducing agents. The gastric and intestinal mucosa are more permeable and/or have greater antioxidant activity on their surface. The reduction of nitroxides in the urinary bladder mucosa occurs via the ascorbate-thiol coupled reducing system.

The study of drug release from microspheres adhered on pig vesical mucosa.

The object of our work is the preparation of a mucoadhesive drug delivery system intended for intravesical application. In the present work, microspheres with Eudragit RS matrix polymer and different mucoadhesive polymers, i.e. chitosan hydrochloride (Ch), sodium salt of carboxymethyl cellulose (CMC) and polycarbophil (PC) were prepared to evaluate their influence on the mucoadhesive properties of microspheres. Different parameters were determined and their influence on pipemidic acid release from microspheres adhered on intact and damaged pig vesical mucosa was evaluated: swelling of polymers, mucoadhesion strength of polymeric films and drug dissolution according to USP XXIV method. The dissolution rate from microspheres containing different mucoadhesive polymers decreases as follows: PC>Ch>CMC. PC swelled to the largest volume among all polymers and as a result the fastest release of the drug from PC microspheres was obtained. The release rate of pipemidic acid from microspheres adhered on intact mucosa followed the order PC>CMC>Ch. These results show that both drug dissolution and mucoadhesion strength strongly influence drug release from adhered microspheres. The slowest release from Ch microspheres could be interpreted by the largest mucoadhesion strength of Ch polymeric films. The release rate of pipemidic acid from microspheres adhered on damaged mucosa followed the order PC=Ch>CMC. The results obtained on pathologically changed mucosa model support the indication of the role of glycosaminoglycans and polymer charge in the mucoadhesion process on vesical mucosa. Analysis of release data shows that the drug dissolution profiles follow the Higuchi kinetics better than the release profiles from adhered microspheres and different kinetics might be a consequence of different release mechanisms.