Cecilia Fernández Lastra

A comparative in vitro study of percutaneous penetration of β-blockers in human skin ☆

In vitro diffusion experiments with propranolol, oxprenolol, metoprolol and atenolol were carried out using excised human abdominal skin. The main permeation parameters (permeability coefficient, flow and lag time) were calculated and compared as measurement of intrinsic permeability across human skin. A long lag time and a low steady-state flow were found for all drugs assayed. Skin permeability predicted at steady state did not reach therapeutic concentrations, which indicated the need for appropriate chemical penetration enhancers or vehicles to overcome limiting factors. The results, including those of celiprolol and bisoprolol reported previously, correlated with physicochemical properties, especially with lipophilicity, one of the main factors in drug permeability prediction through human skin.

Error structure for the HPLC analysis for atenolol, metoprolol and propranolol: a useful weighting method in parameter estimation

Three reversed-phase high performance liquid chromatography (HPLC) methods with UV detection were developed and fully validated for the quantification of three beta-blockers: atenolol, metoprolol and propranolol. After validation, error structures for the HPLC analysis were established using a convenient and practical procedure. The mean percentage of relative standard deviation (RSD) of the experimental concentrations (C), were less than 4.29% for proportionality and less than 3.68% for precision for any of the drugs, which allowed the quantitation of beta-blockers assayed at concentrations in the range 25-0.78 micrograms.ml-1. The error structures for the HPLC analysis were: SD (micrograms.ml-1) = 5.02 x 10(-2) C for atenolol, SD (micrograms.ml-1) = 4.55 x 10(-2) + 0.63 x 10(-2) C - 7.58 x 10(-6) C3 for metoprolol and SD (micrograms.ml-1) = 2.73 x 10(-2) C - 3.49 x 10(-4) C2 for propranolol. The reciprocal of the square of the SD of the drug concentrations measured within the calibration curve could be used as weighting methods in parameter estimation by non-linear regression.

Development and validation of liquid chromatography methods for the quantitation of propranolol, metoprolol, atenolol and bisoprolol: Application in solution stability studies

Four analytical methods have been developed and validated for the quantitation of β-blockers (propranolol, metoprolol, atenolol and bisoprolol) using high-performance liquid chromatography (HPLC) with UV detection. Excellent proportionality, precision and accuracy were achieved by the assays. The use of only one kind of reverse-phase column and a mobile phase for all β-blockers permitted the analysis of a large number of samples in a short time. Their stability in solution was also studied. The results show that the β-blockers assayed are stable for at least 84 h at 90°C.

Determination of analytical error function for β-blockers as a possible weighting method for the estimation of the regression parameters

Three analytical methods have been developed and validated for the quantification of beta-blockers (celiprolol, bisoprolol and oxprenolol) using high performance liquid chromatography (HPLC) with UV detection. The methods were determined to be linear, precise and accurate (RSDs were lower than 5%), which allowed the quantitation of beta-blockers assayed at concentrations in the range 25-0.78 micrograms ml-1. After validation of reversed-phase HPLC methods, their analytical error functions were established by a rapid, simple and economical procedure. The discrimination of the best function for each active principle was performed by an appropriate polynomial statistical analysis, yielding SD (microgram ml-1) = 0.0295 + 0.0124C - 3.88 x 10(-4)C2 for celiprolol, 0.0199 + 0.011C - 1.27 x 10(-5)C3 for bisoprolol; and 0.0183 + 0.0089C - 9.68 x 10(-6)C3 for oxprenolol. These analytical error functions are an alternative to the weighting methods used in parameter estimation of beta-blockers.

Transdermal absorption of celiprolol and bisoprolol in human skin in vitro

Two β-blockers, celiprolol and bisoprolol, which have a priori interesting properties to be considered in the search of a possible candidate for a transdermal therapeutic system (TTS) were assayed. In vitro permeation studies were conducted at 32±1°C across human abdominal skin. Franz glass diffusion cells were used in the static mode (n=7). The amounts of drug permeated from receptor solution at predetermined times were analysed by reversed-phase HPLC with UV detection. From the penetration profiles obtained for each drug, the main permeation parameters, permeability coefficient (Kp), flow (J) and lag time (Tlag) were estimated as a measure of the intrinsic permeability across human skin. Mean Kp value was higher for celiprolol (0.59±0.22 cm h−1) than bisoprolol (0.27±0.15×10−3 cm h−1), although both were very low. Mean J value was also higher for celiprolol (2.72±0.92 μg h−1 cm−2) than bisoprolol (1.19±0.60 μg h−1 cm−2). Mean Tlag value was 20.43±8.43 h for celiprolol and 32.13±39.34 h for bisoprolol. Both provide plasma concentrations at steady state that would be far from their therapeutic concentration. The results indicate the need for appropriate enhancers to improve their diffusion across human skin.

Profile, cost and pattern of prescriptions for polymedicated patients in Catalonia, Spain

Objectives Polypharmacy is one of the main management issues in public health policies because of its financial impact and the increasing number of people involved. The polymedicated population according to their demographic and therapeutic profile and the cost for the public healthcare system were characterised. Design Cross-sectional study. Setting Primary healthcare in Barcelona Health Region, Catalonia, Spain (5 105 551 inhabitants registered). Participants All insured polymedicated patients. Polymedicated patients were those with a consumption of ≥16 drugs/month. Main outcomes measures The study variables were related to age, gender and medication intake obtained from the 2008 census and records of prescriptions dispensed in pharmacies and charged to the public health system. Results There were 36 880 polymedicated patients (women: 64.2%; average age: 74.5±10.9 years). The total number of prescriptions billed in 2008 was 2 266 830 (2 272 920 total package units). The most polymedicated group (up to 40% of the total prescriptions) was patients between 75 and 84 years old. The average number of prescriptions billed monthly per patient was 32±2, with an average cost of €452.7±27.5. The total cost of those prescriptions corresponded to 2% of the drug expenditure in Catalonia. The groups N, C, A, R and M represented 71.4% of the total number of drug package units dispensed to polymedicated patients. Great variability was found between the medication profiles of men and women, and between age groups; greater discrepancies were found in paediatric patients (5–14 years) and the elderly (≥65 years). Conclusions This study provides essential information to take steps towards rational drug use and a structured approach in the polymedicated population in primary healthcare.

Evaluation of electronic prescription implementation in polymedicated users of Catalonia, Spain: a population-based longitudinal study.

Objectives To assess whether electronic prescribing is a comprehensive health management tool that may contribute to rational drug use, particularly in polymedicated patients receiving 16 or more medications in the public healthcare system in the Barcelona Health Region (BHR). Design 16 months of retrospective study followed by 12 months of prospective monitoring. Setting Primary healthcare in BHR, Catalonia, Spain. Participants All insured patients, especially those who are polymedicated in six basic health areas (BHA). Polymedicated patients were those with a consumption of ≥16 drugs/month. Interventions Monitoring demographic and consumption variables obtained from the records of prescriptions dispensed in pharmacies and charged to the public health system, as well as the resulting drug use indicators. Territorial variables related to implementation of electronic prescribing were also described and were obtained from the institutional data related to the deployment of the project. Main outcome measures Trend in drug use indicators (number of prescriptions per polymedicated user, total cost per polymedicated user and total cost per prescription) according to e-prescription implementation. Results There was a significant upward trend in the number of polymedicated users, number of prescriptions and total cost (p<0.05), which seemed independent from the implementation of electronic prescribing when comparing the preimplementation and postimplementation period. Prescriptions per user and cost per user showed a decrease between the preimplementation and postimplementation period, being significant in two BHAs (p<0.05). Conclusions Results suggest that after the implementation of electronic prescribing, the rationality of prescribing in polymedicated patients improved. In addition, this study provides a very valuable approach for future impact assessment.

Determination of celiprolol by high-performance liquid chromatography and stability in solution

An isocratic technique was developed for the analysis of Celiprolol HCl using high-performance liquid chromatography (HPLC) with UV detection and a C18 reverse-phase column. The coefficient of variation (C.V.) for precision and proportionality assays was lower than 5% for all concentrations studied. The stability of the drug in solution was studied. We deduced that the shelf-life (t90%) of Celiprolol HCl at room temperature (25°C) was 13.8 days.

Sequential atomic force microscopy imaging of a spontaneous nanoencapsulation process

Since hydrophilic matrices were proposed for controlled drug delivery, many polymeric excipients have been studied in order to make drug release fit the desired profiles. It has been pointed out that lambda-carrageenan, a sulphated polymer from algae, can suitably control the release rate of basic drugs from hydrophilic matrices with no need for complex technological processes. In this work, we propose a method to monitor morphologically the interaction between lambda-carrageenan and dexchlorpheniramine maleate (D-CPM), in order to find out how the release profiles can be so easily controlled. To this end, solutions of both polymer and drug were prepared at very low concentration. Solutions were mixed and samples were taken every hour over a period of 20 h. The characterization technique employed, atomic force microscopy (AFM), provides a high resolution, allowing to show the three-dimensional morphology of the samples within the nanometric scale. The results demonstrate that lambda-carrageenan is able to nanoencapsulate spontaneously D-CPM molecules, which offers the possibility to easily control the release rate of the drug. This work has moreover demonstrated the suitability of AFM for the specific case of the on-time monitoring of interaction processes that happen in pharmaceutical systems.

Readability Analysis of the Package Leaflets for Biological Medicines Available on the Internet Between 2007 and 2013: An Analytical Longitudinal Study

Background The package leaflet included in the packaging of all medicinal products plays an important role in the transmission of medicine-related information to patients. Therefore, in 2009, the European Commission published readability guidelines to try to ensure that the information contained in the package leaflet is understood by patients. Objective The main objective of this study was to calculate and compare the readability levels and length (number of words) of the package leaflets for biological medicines in 2007, 2010, and 2013. Methods The sample of this study included 36 biological medicine package leaflets that were downloaded from the European Medicines Agency website in three different years: 2007, 2010, and 2013. The readability of the selected package leaflets was obtained using the following readability formulas: SMOG grade, Flesch-Kincaid grade level, and Szigriszt’s perspicuity index. The length (number of words) of the package leaflets was also measured. Afterwards, the relationship between these quantitative variables (three readability indexes and length) and categorical (or qualitative) variables were analyzed. The categorical variables were the year when the package leaflet was downloaded, the package leaflet section, type of medicine, year of authorization of biological medicine, and marketing authorization holder. Results The readability values of all the package leaflets exceeded the sixth-grade reading level, which is the recommended value for health-related written materials. No statistically significant differences were found between the three years of study in the readability indexes, although differences were observed in the case of the length (P=.002), which increased over the study period. When the relationship between readability indexes and length and the other variables was analyzed, statistically significant differences were found between package leaflet sections (P<.001) and between the groups of medicine only with regard to the length over the three studied years (P=.002 in 2007, P=.007 in 2010, P=.009 in 2013). Linear correlation was observed between the readability indexes (SMOG grade and Flesch-Kincaid grade level: r2=.92; SMOG grade and Szigriszt’s perspicuity index: r2=.81; Flesch-Kincaid grade level and Szigriszt’s perspicuity index: r2=.95), but not between the readability indexes and the length (length and SMOG grade: r2=.05; length and Flesch-Kincaid grade level: r2=.03; length and Szigriszt’s perspicuity index: r2=.02). Conclusions There was no improvement in the readability of the package leaflets studied between 2007 and 2013 despite the European Commission’s 2009 guideline on the readability of package leaflets. The results obtained from the different readability formulas coincided from a qualitative point of view. Efforts to improve the readability of package leaflets for biological medicines are required to promote the understandability and accessibility of this online health information by patients and thereby contribute to the appropriate use of medicines and medicine safety.