Thierry Van Hees

Application of Supercritical Carbon Dioxide for the Preparation of a Piroxicam-β-Cyclodextrin Inclusion Compound

AbstractPurpose. Piroxicam is a poorly soluble NSAID, whose solubility is enhanced when included into β-cyclodextrin. The preparation of a piroxicam-β-cyclodextrin inclusion compound using supercritical CO2 was investigated. Methods. The solubility and the stability of piroxicam in supercritical CO2 were determined. Then, the influence of the temperature, the pressure and the time of exposure on the inclusion rate was studied. Results. The solubility of piroxicam varied over a wide range depending on the temperature and pressure (from 0.006 to 1.500 mg/g of CO2). The temperature and the time of exposure had a great influence on the inclusion yield, while pressure did not and a complete inclusion was achieved by keeping a physical mixture of piroxicam and β-cyclodextrin (1:2.5 mol/mol) for 6 hours at 150°C and 15 MPa of CO2. This complex was characterized by Differential Scanning Calorimetry, differential solubility and Fourier Transform Infrared Spectrometry. Conclusions. Supercritical carbon dioxide may prove to be a novel useful complexation method of drugs into β-cyclodextrin.

Effectiveness of pharmaceutical care for patients with chronic obstructive pulmonary disease (PHARMACOP): a randomized controlled trial

AIMS Few well-designed randomized controlled trials have been conducted regarding the impact of community pharmacist interventions on pharmacotherapeutic monitoring of patients with chronic obstructive pulmonary disease (COPD). We assessed the effectiveness of a pharmaceutical care programme for patients with COPD. METHODS The pharmaceutical care for patients with COPD (PHARMACOP) trial is a single-blind 3 month randomized controlled trial, conducted in 170 community pharmacies in Belgium, enrolling patients prescribed daily COPD medication, aged ≥ 50 years and with a smoking history of ≥ 10 pack-years. A computer-generated randomization sequence allocated patients to an intervention group (n = 371), receiving protocol-defined pharmacist care, or a control group (n = 363), receiving usual pharmacist care (1:1 ratio, stratified by centre). Interventions focusing on inhalation technique and adherence to maintenance therapy were carried out at start of the trial and at 1 month follow-up. Primary outcomes were inhalation technique and medication adherence. Secondary outcomes were exacerbation rate, dyspnoea, COPD-specific and generic health status and smoking behaviour. RESULTS From December 2010 to April 2011, 734 patients were enrolled. Forty-two patients (5.7%) were lost to follow-up. At the end of the trial, inhalation score [mean estimated difference (Δ),13.5%; 95% confidence interval (CI), 10.8-16.1; P < 0.0001] and medication adherence (Δ, 8.51%; 95% CI, 4.63-12.4; P < 0.0001) were significantly higher in the intervention group compared with the control group. In the intervention group, a significantly lower hospitalization rate was observed (9 vs. 35; rate ratio, 0.28; 95% CI, 0.12-0.64; P = 0.003). No other significant between-group differences were observed. CONCLUSIONS Pragmatic pharmacist care programmes improve the pharmacotherapeutic regimen in patients with COPD and could reduce hospitalization rates.

Determination of the free/included piroxicam ratio in cyclodextrin complexes: comparison between UV spectrophotometry and differential scanning calorimetry

Few analytical techniques allow to evaluate the inclusion yield of cyclodextrin-drug complexes, because most manufacturing processes give amorphous products. In this study, we have developed an alternative method to differential scanning calorimetry, to accurately determine the free/complexed piroxicam ratio by UV spectroscopy. This method is based on the differential solubility of the piroxicam-beta-cyclodextrin 1:2.5 mol/mol complex in water-acetonitrile (1:1, v/v) (Solvent A) or in anhydrous acetonitrile (Solvent B), both containing 0.05 M HCl. In anhydrous acetonitrile, beta-cyclodextrin is insoluble and the included drug remains entrapped, allowing the free piroxicam determination, while with 50% of water, the complex is totally dissolved, allowing the determination of the total guest content. This method was validated for linearity, precision and accuracy. The presence of cyclodextrin does not influence the assays, but more than 0.5% of water in Solvent B significantly affects the determination of the free piroxicam content. In comparison with differential scanning calorimetry, both detectability and precision were improved. It is now possible to analyse complexes with an inclusion purity greater than 99%.

Effectiveness of PHARMAceutical care for patients with COPD (PHARMACOP): a randomized controlled trial

AIMS Few well-designed randomized controlled trials have been conducted regarding the impact of community pharmacist interventions on pharmacotherapeutic monitoring of patients with chronic obstructive pulmonary disease (COPD). We assessed the effectiveness of a pharmaceutical care programme for patients with COPD. METHODS The pharmaceutical care for patients with COPD (PHARMACOP) trial is a single-blind 3 month randomized controlled trial, conducted in 170 community pharmacies in Belgium, enrolling patients prescribed daily COPD medication, aged ≥ 50 years and with a smoking history of ≥ 10 pack-years. A computer-generated randomization sequence allocated patients to an intervention group (n = 371), receiving protocol-defined pharmacist care, or a control group (n = 363), receiving usual pharmacist care (1:1 ratio, stratified by centre). Interventions focusing on inhalation technique and adherence to maintenance therapy were carried out at start of the trial and at 1 month follow-up. Primary outcomes were inhalation technique and medication adherence. Secondary outcomes were exacerbation rate, dyspnoea, COPD-specific and generic health status and smoking behaviour. RESULTS From December 2010 to April 2011, 734 patients were enrolled. Forty-two patients (5.7%) were lost to follow-up. At the end of the trial, inhalation score [mean estimated difference (Δ),13.5%; 95% confidence interval (CI), 10.8-16.1; P < 0.0001] and medication adherence (Δ, 8.51%; 95% CI, 4.63-12.4; P < 0.0001) were significantly higher in the intervention group compared with the control group. In the intervention group, a significantly lower hospitalization rate was observed (9 vs. 35; rate ratio, 0.28; 95% CI, 0.12-0.64; P = 0.003). No other significant between-group differences were observed. CONCLUSIONS Pragmatic pharmacist care programmes improve the pharmacotherapeutic regimen in patients with COPD and could reduce hospitalization rates.

Application of Supercritical carbon dioxide for the preparation of drug-cyclodextrin inclusion compounds

Inclusion complexes of drugs into cyclodextrins (CDs) can be obtained at the solid state by means of supercritical dioxide (SCCO2). A successful inclusion with a yield >98.5% has been achieved with piroxicam and β-CD. The temperature and the time of exposure to SCCO2 have a significant effect on the inclusion yield while the pressure has a negative effect. However, there is a strong interaction between temperature and pressure and this interaction has a positive influence. The molar ratio piroxicam-β-CD and the addition of ternary alkaline agents were also found to be significant factors. The dissolution rate of the complexes formed using SCCO2 was found to be significantly higher than that of the physical mixture. Inclusion complexes have also been obtained with miconazole treating mixtures of miconazole, CDs and citric acid by SCCO2. This new technique of inclusion of poorly soluble drugs into CDs allows the preparation of solid complexes without using organic solvents and thus without residues.

Detailed analysis of sputum and systemic inflammation in asthma phenotypes: are paucigranulocytic asthmatics really non-inflammatory?

BackgroundThe technique of induced sputum has allowed to subdivide asthma patients into inflammatory phenotypes according to their level of granulocyte airway infiltration. There are very few studies which looked at detailed sputum and blood cell counts in a large cohort of asthmatics divided into inflammatory phenotypes. The purpose of this study was to analyze sputum cell counts, blood leukocytes and systemic inflammatory markers in these phenotypes, and investigate how those groups compared with healthy subjects.MethodsWe conducted a retrospective cross-sectional study on 833 asthmatics recruited from the University Asthma Clinic of Liege and compared them with 194 healthy subjects. Asthmatics were classified into inflammatory phenotypes.ResultsThe total non-squamous cell count per gram of sputum was greater in mixed granulocytic and neutrophilic phenotypes as compared to eosinophilic, paucigranulocytic asthma and healthy subjects (p < 0.005). Sputum eosinophils (in absolute values and percentages) were increased in all asthma phenotypes including paucigranulocytic asthma, compared to healthy subjects (p < 0.005). Eosinophilic asthma showed higher absolute sputum neutrophil and lymphocyte counts than healthy subjects (p < 0.005), while neutrophilic asthmatics had a particularly low number of sputum macrophages and epithelial cells. All asthma phenotypes showed an increased blood leukocyte count compared to healthy subjects (p < 0.005), with paucigranulocytic asthmatics having also increased absolute blood eosinophils compared to healthy subjects (p < 0.005). Neutrophilic asthma had raised CRP and fibrinogen while eosinophilic asthma only showed raised fibrinogen compared to healthy subjects (p < 0.005).ConclusionsThis study demonstrates that a significant eosinophilic inflammation is present across all categories of asthma, and that paucigranulocytic asthma may be seen as a low grade inflammatory disease.

Inclusion Complexes of Cyproterone Acetate with Cyclodextrins in Aqueous Solution

Cyproterone acetate (CPA) is a steroidal antiandrogen with a progestogenic activity. Given that this molecule has a very poor water solubility (2.1 μg/mL), different cyclodextrins (CDs) were tested to form inclusion complexes and to increase solubility. Two different techniques were compared to study the affinity between CPA and CDs: phase-solubility studies and NMR spectroscopy. The stoichiometry and the stability constant could be determined for most complexes with the aid of phase-solubility studies. The greatest increase in solubility was achieved with the methylated β-CDs, but hydroxypropylated β- and γ-CDs also gave enhanced solubilities. 1H-NMR studies showed a solubility increase similar to that found with phase-solubility studies. The proof of inclusion in the2,6-dimethyl-β-CD (DIMEB) was shown by 1H-NMR and t-ROESY spectra.

Community pharmacists' evaluation of potentially inappropriate prescribing in older community-dwelling patients with polypharmacy: observational research based on the GheOP³S tool

Background In this study, we aimed to (i) determine the prevalence of potentially inappropriate prescribing (PIP) in community‐dwelling older polypharmacy patients using the Ghent Older Peoples Prescriptions community‐Pharmacy Screening (GheOP3S) tool, (ii) identify the items that account for the highest proportion of PIP and (iii) identify the patient variables that may influence the occurrence of PIP. Additionally, pharmacist‐physician contacts emerging from PIP screening with the GheOP3S tool and feasibility of the GheOP3S tool in daily practice were evaluated. Methods A prospective observational study was carried out between December 2013 and July 2014 in 204 community pharmacies in Belgium. Patients were eligible if they were (i) ≥70 years, (ii) community‐dwelling, (iii) using ≥5 chronic drugs, (iv) a regular visitor of the pharmacy and (v) understanding Dutch or French. Community pharmacists used a structured interview to obtain demographic data and medication use and subsequently screened for PIP using the GheOP3S tool. A Poisson regression was used to investigate the association between different covariates and the number of PIP. Results In 987 (97%) of 1016 included patients, 3721 PIP items were detected (median of 3 per patient; inter quartile range: 2‐5). Most frequently involved with PIP are drugs for the central nervous system such as hypnosedatives, antipsychotics and antidepressants. Risk factors for a higher PIP prevalence appeared to be a higher number of drugs (30% extra PIPs per 5 extra drugs), female gender (20% extra PIPs), higher body mass index (BMI, 20% extra PIPs per 10‐unit increase in BMI) and poorer functional status (30% extra PIPs with 6‐point increase). The feasibility of the GheOP3S tool was acceptable although digitalization of the tool would improve implementation. Despite detecting at least one PIP in 987 patients, only 39 physicians were contacted by the community pharmacists to discuss the items. Conclusion A high prevalence of PIP in community‐dwelling older polypharmacy patients in Belgium was detected which urges for interventions to reduce PIP.

Is it possible to claim or refute sputum eosinophils ≥ 3% in asthmatics with sufficient accuracy using biomarkers?

The concept of asthma inflammatory phenotypes has proved to be important in predicting response to inhaled corticosteroids. Induced sputum, which has been pivotal in the development of the concept of inflammatory phenotypes, is however not widely available. Several studies have proposed to use surrogate exhaled or blood biomarkers, like fractional exhaled nitric oxide (FENO), blood eosinophils and total serum immunoglobulin E (IgE). However, taken alone, each of these biomarkers has moderate accuracy to identify sputum eosinophilia. Here, we propose a new approach based on the likelihood ratio to study which thresholds of these biomarkers, taken alone or in combination, were able to rule in or rule out sputum eosinophils ≥3%. We showed in a large population of 869 asthmatics that combining FENO, blood eosinophils and total serum IgE could accurately predict sputum eosinophils ≥ or <3% in 58% of our population.

Influence of cyclodextrins on the solubility and the pharmacokinetics of albendazole

Albendazole (ABZ) is a benzimidazole derivative with a broad spectrum of activity against human and animal helminthe parasites. The ABZ therapy is very important in systemic cestode infection specially in inoperable or disseminated cases of hydatosis [1]. The main problem encountered with benzimidazoles is their low and erratic bioavailability owing to their low aqueous solubility.