Aleš Mrhar

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.

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.

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.

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.

Investigation of the Influence of CYP1A2 and CYP2C19 Genetic Polymorphism on 2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)- 2-butenamide (A77 1726) Pharmacokinetics in Leflunomide- Treated Patients with Rheumatoid Arthritis

Leflunomide is a disease-modifying antirheumatic drug used for the treatment of rheumatoid arthritis (RA). Cytochromes P450, mainly CYP1A2 and CYP2C19, may be involved in the transformation of leflunomide to leflunomide metabolite (A77 1726, 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide). The aim of this study was to investigate whether genetic polymorphisms in CYP1A2 and CYP2C19 influence leflunomide pharmacokinetics, treatment response, and the occurrence of adverse drug reactions (ADRs). The study included 67 patients with RA and 4 patients with polyarthritis resembling RA and psoriasis treated with leflunomide. A77 1726 steady-state plasma concentrations were determined by validated high-performance liquid chromatography with UV detection. A population pharmacokinetic model was developed to estimate the oral clearance (CL/F) and volume of distribution (V/F). A genotyping approach was used to determine C-163A, C-729T, and T-739G in the CYP1A2 gene as well as single nucleotide polymorphisms that characterize CYP2C19*2, *3, *4, and *17 alleles. A large interindividual variability in trough A77 1726 steady-state plasma concentrations was observed (from 1.9 to 156.9 mg/l). A77 1726 CL/F was 71% higher in carriers of the CYP2C19*2 allele compared with noncarriers. The A77 1726 average steady-state plasma concentration was associated with the treatment response. Patients with a greater decrease in C-reactive protein (CRP) had higher average steady-state plasma A77 1726 concentrations: 49.7 ± 39.0 mg/l in patients with ΔCRP of more than 8.5 mg/l compared with 24.8 ± 13.7 mg/l in patients with ΔCRP of ≤8.5 mg/l (p = 0.015). No association of A77 1726 steady-state plasma concentrations with the occurrence of ADRs was observed. Our results suggest that genetic variability in leflunomide-metabolizing enzymes influences leflunomide metabolite concentrations that are associated with the treatment response but not with leflunomide-induced toxicity.

Cost-effectiveness of UGT1A1 genotyping in second-line, high-dose, once every 3 weeks irinotecan monotherapy treatment of colorectal cancer.

AIM The aim of the present study was to evaluate the cost-effectiveness of UGT1A1 genotyping in second-line, high-dose, once every 3 weeks irinotecan monotherapy treatment of colorectal cancer. METHODS Standard therapy was compared with alternative strategies based on UGT1A1 genotyping from the US healthcare payer perspective. Two alternative strategies (dose reduction and prophylactic use of G-CSF with prior genotyping) and standard therapy were evaluated in a decision analysis, whereas alternative regimens were considered in discussion. The effectiveness outcome was severe neutropenia occurrence and number of life-years gained. RESULTS & CONCLUSION Genotyping in combination with a subsequent reduction of initial irinotecan dose for UGT1A1 7/7 genotype patients was cost-saving for the population of African and Caucasian origin. By contrast, UGT1A1 genotyping was not cost effective for the population of Asian ancestry. Furthermore, the prophylactic use of G-CSFs in UGT1A1 7/7 genotype patients was not cost effective in any population group. Finally, the application of a 3-weekly high-dose treatment regimen with a 20% reduced dosage compared with the low-dose weekly irinotecan regimen in patients with UGT1A1 7/7 genotype was less expensive and is more convenient for the patient.

Influence of physicochemical and biological parameters on drug release from microspheres adhered on vesical and intestinal mucosa.

The object of our work is to develop mucoadhesive microspheres to be applied into the urinary bladder. In the present study the microspheres were prepared and the release of a model drug after their adhesion to mucosa was evaluated. The microspheres were prepared by solvent evaporation method using Eudragit RL or hydroxypropylcellulose as matrix polymers and one out of five different polymers as mucoadhesives or non-mucoadhesive references. A method for the evaluation of the drug release from microspheres adhered on guinea pig urinary bladder and small intestine mucosa was developed and the influence of the following parameters on this process was followed: mucoadhesion strength of polymeric films, swelling of polymers and the drug release from microspheres. The results showed that the detachment forces were decreasing in the following order: CMCNa > Carbopol 934P > HPC > EE.HCl = PVP/VA. Carbopol swelled to the largest volume among all polymers and the drug release from microspheres was more retarded when Eudragit RL was used as matrix polymer. When comparing the results of pipemidic acid release from microspheres adhered on intestinal mucosa with detachment forces, similar ratios among the mucoadhesive polymers can be seen. On the other hand, differences between two mucosae were observed. These differences are due to the amount of mucus on mucosa and might also be influenced by the charge of mucus. The goal of our work at this point of investigation was achieved by microspheres containing carboxymethylcellulose as mucoadhesive and Eudragit RL as matrix polymer because they provide the longest release time from microspheres adhered on vesical mucosa and sufficient high strength of mucoadhesion.

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 payers perspective.

The need for medication reconciliation: a cross-sectional observational study in adult patients

BACKGROUND Poor communication of drug therapy at care interface often results in medication errors and adverse drug events. Medication reconciliation has been introduced as a measure to improve continuity of patient care. The aim of this cross-sectional observational study was to evaluate the need for medication reconciliation. METHODS Comprehensive information on pre-admission therapy was obtained by a research pharmacist for adult medical patients, admitted to a teaching hospital, specialised in pulmonary and allergic diseases, in Slovenia. This information was compared with the in-patient and discharge therapies to identify unintentional discrepancies (medication errors) whose clinical significance was determined by an expert panel reaching consensus. RESULTS Most of the included 101 patients were elderly (median age: 73 years) who had multiple medications. Among their in-patient drugs (880), few discrepancies were a medication error (54/654), half of which were judged to be clinically important. A higher rate was observed in the discharge drug therapy (747): 369 of the identified discrepancies (566) were a medication error, over half of which were judged as clinically important. A greater number of pre-admission drugs, poorly taken medication histories and a greater number of medication errors in in-patient therapy predisposed patients to clinically important medication errors in discharge therapy. CONCLUSIONS This study provided evidence in a small sample of patients on the discontinuity of drug therapy at patient discharge in a hospital in Slovenia and its implications for patient care. To ensure continuity and safety of patient care, medication reconciliation should be implemented throughout a patients hospital stay.

A population pharmacokinetic evaluation of the influence of CYP2D6 genotype on risperidone metabolism in patients with acute episode of schizophrenia

The objective of this prospective study was to characterize the metabolism of risperidone to (+)- and (-)-9-hydroxyrisperidone in vivo and to evaluate the influence of CYP2D6 genotype. A population pharmacokinetic modeling approach was used to estimate the interindividual variability of the pharmacokinetic parameters in 50 hospitalized patients with acute episode of schizophrenia. CYP2D6 genotype remarkably influenced the formation clearances of the risperidone metabolites, while creatinine clearance was related to the plasma clearance of 9-hydroxyrisperidone. CYP2D6 genotype was also associated with the average plasma concentration of risperidone active moiety (a sum of all three active compounds). In comparison to the patients with CYP2D6*1/*1 genotype, average steady-state plasma concentration of risperidone active moiety was 3.3- and 1.6-fold higher in poor metabolizers (both alleles nonfunctional; CYP2D6*3 or *4) and intermediate metabolizers (one nonfunctional allele and one allele for diminished enzyme activity; CYP2D6*10 or *41), respectively. Additionally, average plasma concentration of risperidone active moiety was higher in the patients with dystonia (p=0.0066) and parkinsonism (p=0.046). The results of this study imply the potential role of CYP2D6 genotyping in personalizing risperidone therapy in patients with schizophrenia to reduce the incidence of adverse extrapyramidal symptoms.