Microspheres containing the mucoadhesive polymer chitosan hydrochloride, with matrix polymer Eudragit RS, pipemidic acid as a model drug and agglomeration preventing agent magnesium stearate were ...prepared by the solvent evaporation method. The amount of magnesium stearate was varied and the following methods were used for microsphere evaluation: sieve analysis, drug content and dissolution determination, scanning electron microscopy, xray diffractometry, DSC and FTIR spectroscopy. The results showed that average particle size decreased with increasing amount of magnesium stearate used for microsphere preparation. This is probably a consequence of stabilization of the emulsion droplets with magnesium stearate. Higher pipemidic acid content in the microspheres was observed in larger particle size fractions and when higher amounts of magnesium stearate were used. It was also found that these two parameters significantly influenced the dissolution rate. The important reason for the differences in drug content in microspheres of different particle sizes is the diffusion of pipemidic acid from the acetone droplets in liquid paraffin during the preparation procedure. The physical state of pipemidic acid changed from crystalline to mostly amorphous with its incorporation in microspheres, as shown by x-ray diffractometry and differential
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
≤
2.38% and CV
≤
7.93%, respectively) was demonstrated in the range of 0.5–10
mg
L
−1 for both detectors. The presented method was applied without any interference of excipients to the determination of raloxifene hydrochloride content in tablets and to the in vitro dissolution studies. The proposed method could be used for routine quality control.
Moreover, due to its low LOQ, excellent accuracy, precision and selectivity, the coulometric detection could be applied to in vitro metabolism experiments such as microsome or hepatocyte preparations and for studies of transport of raloxifene hydrochloride across biological membranes.
Chitosan is a cationic polysaccharide widely employed as an absorption enhancer. The aim of this work was to examine the effect of chitosan on the permeability of isolated pig urinary bladder wall as ...well as to determine the role of calcium ions in this process. Besides permeability studies, scanning electron microscopy and fluorescent microscopy were applied to get an insight into the mechanism by which chitosan increases the permeability of urinary bladder wall. Additionally, the obtained findings were compared to the mechanism proposed for Caco-2 cells. The results show that 0.5% (w/v) chitosan increases the permeability of urinary bladder wall by causing the desquamation of the urothelium. Calcium ions, when applied to the luminal surface of the urinary bladder at the same time as chitosan, decreases the effect of chitosan on permeation of the model drug moxifloxacin into the bladder wall in concentration dependent way. The desquamation of urothelium cells caused by chitosan was reduced in the presence of calcium, but not to such extent as it would be expected from the permeability studies. When present, calcium obviously interferes directly in the interactions between chitosan and the surface of urothelium.
Background: The objective of the present study is to evaluate the cost-effectiveness of human papillomavirus (HPV) vaccination alongside cervical cancer screening programme in Slovenia. Methods: A ...previously published Markov model representing natural history of HPV infection was adapted to Slovenian context. The model followed a cohort of 12-year-old girls to 85-year-old women. Two strategies were compared: HPV vaccination alongside conventional cytological screening versus screening alone. Analysis was performed from the health care payer perspective. Results: Vaccination with screening compared with screening alone was associated with an incremental cost-effectiveness ratio (ICER) of 23 178 EUR per quality adjusted life-year (QALY) gained and 54 536 EUR per life-year gained (LYG) at the discounting rate of 5%. Sensitivity analyses demonstrated that the ICER was most sensitive to the need for booster dose and to different values of discount rates. In case the booster dose was assumed 10 years after initial vaccination, the ICER value was increased to 58 690 EUR per QALY. On the other hand, using lower values of discount rates than the base case 5% significantly reduced the ICER value. Conclusion: According to the cost-effectiveness thresholds of 30 000 EUR per QALY which was adopted by the Health Council in Slovenia, HPV vaccination alongside screening programme can be regarded as cost-effective. However, cost-effectiveness of HPV vaccination would become questionable in case a booster dose was needed to provide lifetime protection.
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.
The detachment forces of various polymers are frequently measured to determine their mucoadhesion strength. As the process of mucoadhesion is a consequence of interactions between the mucus layer on ...mucosa and mucoadhesive polymers, it is greatly dependent on mucus and polymer structure including their charge. It is also known that the glycosaminoglycan layer, which covers the urinary bladder mucosa surface, is highly negatively charged. Therefore, by measuring the zeta potential of polymer dispersions and mucosal homogenates an insight into electrostatic interactions during mucoadhesion can be obtained. In our experiments we chose three polymers, two anionic (polycarbophil, PC; sodium carboxymethyl cellulose, CMCNa) and one cationic (chitosan hydrochloride, CH), for which we expected different zeta potential values and different mucoadhesion strengths. The correlation between the zeta potential and the detachment force was determined. In addition to that, the zeta potential of the scraped surface layer of pig urinary bladders was measured to confirm its negative value. The mucoadhesion strength decreased in the following order: CH>CMCNa=PC. The zeta potentials for all three polymers and for porcine vesical mucosal homogenates were measured in Tyrode solution and two NaCl solutions with different ionic strengths. The lower values of the detachment force correlated well with the more negative zeta potential of the polymer, which might be a consequence of the greater repulsion between negative charges of polymers and glycosaminoglycans.
An in vivo investigation of paracetamol availability was carried out on eight healthy volunteers, comparing two paracetamol suppository formulations prepared using two different gliceride bases, a ...fast drug-releasing one and a slow drug-releasing one, i.e. Witepsol H15 and W35, respectively. The formulations were selected on the basis of a previous in vitro drug release study, which showed that, by superimposing the excipients in two layers within the same suppository, the drug release kinetics could be modulated using different ratios between the two layers. The comparison between the two different formulations in terms of plasma profiles and total amounts of drug excreted in urine revealed an increase in the extent of drug absorption from the layered excipient suppository. As the W35 has a higher monoglyceride content than the H15, this improved paracetamol availability could be ascribed to the absorption-enhancing effect of the monoglycerides. Moreover, the W35 has also a higher viscosity, which could possibly cause the suppository to be retained for a longer time in the lower part of the rectum, where the blood is drained directly to the systemic circulation. It was therefore hypothesized that the enhanced paracetamol availability could be also due to a liver bypass mechanism. For a further examination of the paracetamol absorption kinetics after rectal administration, a one-compartment model was fitted to the drug plasma concentration data. This approach allowed to draw absorption versus time profiles, which showed that a retardation actually occurred in paracetamol absorption when using suppositories containing the slow drug releasing excipient W35. These absorption data were then employed for an A level in vitro–in vivo correlation testing, and a linear relationship was found between in vitro release rate and in vivo absorption rate, both for fast releasing and for the layered excipient suppositories.
Influence of globalization can be observed practically everywhere, also in an everyday life of each individual, where long working time, unhealthy nutrition habits, stress and lack of recreation have ...an important influence to people’s health. The consequences can be observed not only in epidemic extensions of chronic diseases (diabetes type-2, hypercholesterolemia, hypertension) but also in increased number of patients with serious health complications. Their treatment represents an immense social and economical burden. In this paper simulation results are presented which can be used for evaluation of patients’ number with coronary heart disease, congestive heart failure and end-stage renal disease in Slovenia. At the same time also year treatment costs were calculated regarding each of observed diseases. Finally the presented results enable the estimation of potential savings resulting from more intensive chronic diseases treatment. The extrapolation is also suggested, with which the results can be extended to the countries with similar demographic and social situation. Resembling circumstances can be expected in practically all the EU countries.
Warfarin is a frequently used anticoagulant drug with narrow therapeutic index and high interindividual variability in the dose requirement. We have previously shown that warfarin dose is influenced ...by cytochrome P450 (CYP) 2C9 genotype, age, body weight and co-treatment with drugs that interfere with warfarin metabolism. As, in many patients, drug co-treatment cannot be avoided, we investigated the effect of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance dose.
Caucasian patients on stable maintenance warfarin therapy with CYP2C9*1/*1 genotype (n=82) were included in the study. Plasma concentrations of (S)- and (R)-warfarin as well as warfarin hydroxylated metabolites were determined using HPLC assay and corresponding clearances of (S)- and (R)-warfarin were calculated.
Patients co-treated with carbamazepine (n=5) had significantly higher plasma 10-hydroxywarfarin concentrations than patients not taking any interacting drugs (n=54) (median: 0.327 microg/ml vs 0.030 microg/ml, p=0.003). (S)- and (R)-warfarin clearances were also higher in the carbamazepine co-treated group (p=0.003), as were warfarin dose requirements (median: 9.00 mg/day vs 3.86 mg/day, p=0.003). Under the conditions of this study, patients co-treated with amiodarone (n=6) did not differ significantly regarding any measured characteristic from patients with no interacting drug treatment, while patients co-treated with simvastatin or lovastatin (n=17) had lower 10-hydroxywarfarin concentration (p=0.02).
We confirmed important interaction between carbamazepine and warfarin metabolism which can be of major clinical importance. If treatment with carbamazepine cannot be avoided, patients taking warfarin should be frequently monitored, especially when initiating or stopping carbamazepine therapy.
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