Dry powder inhalers: study of the parameters influencing adhesion and dispersion of fluticasone propionate.

Interactions between particles are dependent on the physicochemical characteristics of the interacting particles but it is also important to consider the manufacturing process. Blending active pharmaceutical ingredient (API) with carrier is a critical stage that determines the blend homogeneity and is the first step towards obtaining the final quality of the powder blend. The aim of this work was to study parameters that influence the interactions between API and carrier in adhesive mixtures used in DPI and their effect on API dispersion. The study was done with fluticasone propionate blended with lactose 'Lactohale 200'. The study was based on the influence of the operating conditions (speed, mixing time, resting steps during mixing), the size of the carrier and the storage conditions on the blend properties and on the API dispersion. The quality of the blends was examined by analysing the API content uniformity. Adhesion characteristics were evaluated by submitting mixtures to a sieving action by air depression with the Alpine air-jet sieve. Aerodynamic evaluation of fine particle fraction (FPF) was obtained using a Twin Stage Impinger; the FPF being defined as the mass percentage of API below 6.4 µm. For good dispersion and therefore good homogeneity of the API in the carrier particles, speed and powder blending time have to be sufficient, but not too long to prevent the appearance of static electricity, which is not favourable to homogeneity and stability. The FPF increases with the decrease in the carrier size. The storage conditions have also to be taken into consideration. Higher humidity favours the adhesion of API on the carrier and decreases the FPF.

In vitro evaluation of powders for inhalation: the effect of drug concentration on particle detachment.

Limited information on the effect of the drug concentration on the performance of powders for inhalation is currently published. The aim of this work was to study the influence of drug concentration on the adhesion between drug and carrier and on the drug detachment from the carrier. The study was done with formoterol fumarate and fluticasone propionate blended with lactose Lactohale 200. To assess the adhesion of respirable-sized drug to carrier particles, a simple method was developed based on aspiration and considering the whole blend as it is used in dry powder inhalers. Adhesion characteristics were evaluated by submitting the mixtures to a sieving action by air depression with an Alpine air-jet sieve. Aerodynamic evaluation of fine particle dose and emitted dose was obtained using a Twin Stage Impinger (TSI). Drug concentration of powder blends used in dry powder inhalers influenced adhesion, content uniformity and in vitro deposition of the drug. For the higher concentration of formoterol, it seemed that a lower quantity of drug adhered to the lactose. This was confirmed by the aerosolization assays done in the TSI. The fine particle fraction increased linearly with the formoterol concentration. A correlation was observed between adhesion characteristics and inertial impaction. In the case of fluticasone, the influence of the concentration was different. First, the fine particle fraction increased with the concentration and then decreased with a further increase of the fluticasone concentration. This could be explained by the lack of homogeneity when the fluticasone concentration was high because of agglomerates of pure drug which can not be redispersed, or by the physico-chemical characteristics of this drug.

Bone implants modified with cyclodextrin: study of drug release in bulk fluid and into agarose gel.

The aim of this work was to better understand the importance of the type of experimental setup used to monitor antibiotic release from functionalized hydroxyapatite implants. Microporous hydroxyapatite discs were prepared by sintering and subsequently functionalized with hydroxypropyl-ß-cyclodextrin (HPßCD) polymer crosslinked with butanetetracarboxylic acid. On one hand, polymerization was performed within the implant after its impregnation with the monomers (CD-HA-M implant). On the other hand, a pre-synthesized HPßCD polymer was loaded and fixed onto the HA discs (CD-HA-P implant). Both types of implants were soaked with ciprofloxacin hydrochloride or vancomycin hydrochloride solution and dried at 37°C. The DSC study highlighted that the cyclodextrin polymer could interfere with both drugs, due to the carboxylic groups carried by the crosslinks. Drug release was measured into phosphate buffered saline pH 7.4 in agitated vials, or into agarose gels to more realistically mimic in vivo conditions. Importantly, in all cases, drug release into agarose gels was much slower than into well-agitated phosphate buffer. Non-functionalized discs displayed faster drug release because no complex could be formed and/or due to the absence of the HPßCD polymer network hindering drug diffusion within the implant pores. In the case of ciprofloxacin hydrochloride, drug release from the CD-HA-M implants was faster than drug release from the CD-HA-P implants due to the different polymer structures resulting in different complexation strengths, whereas in the case of vancomycin hydrochloride the release patterns were similar because vancomycin hydrochloride was not included into the cyclodextrin. The agarose gel method seems more biorelevant and discriminatory than the vial method for drug release measurements from bone implants.

Health-related quality of life in long-term oxygen-treated chronic obstructive pulmonary disease patients.

Chronic obstructive pulmonary disease (COPD) induces changes in daily activities and mood. Health-related quality of life (HRQL) measures are of particular relevance in the management of such patients, but predictors of HRQL have rarely been investigated. The aim of this study was to seek factors predicting HRQL in severe COPD patients under long term oxygen therapy (LTOT). The pulmonary function parameters at the start of LTOT were studied as potential predictors of future HRQL. HRQL was assessed after an average of 40 months follow-up by the Duke Health Profile (Duke) and by the St. George Respiratory Questionnaire (SGRQ). Sixty-one patients (47 males and 14 females) with a mean age of 66 years were included in the study. Stepwise multiple regression analyses conducted in each HRQL dimension identified few significantly predictive factors. By the Duke, higher Self-esteem scores were associated with higher Pao2 (p < 0.01) and with older age (p < 0.05); higher Social Health scores were associated with older age (p < 0.005), and higher Pain scores were associated with a higher FEV1/FVC ratio (p < 0.05). By the SGRQ, the Activity score correlated with FEV1/FVC (p < 0.05). The proportion of the variance in each score accounted for by covariates in the model did not exceed 10%. No other significant regression models could be identified using the other HRQL dimensions. Our findings demonstrated weak relations between lung function at the start of LTOT and some dimensions of HRQL measured by the Duke and the SGRQ at the end of follow-up.

[Validation of the St George's questionnaire for measuring the quality of life in patients with chronic obstructive pulmonary disease]. / Validation du questionnaire St Georges pour mesurer la qualité de vie chez les insuffisants respiratoires chroniques.

The validity of a French version of a disease specific quality of life instrument, the St George's Respiratory Questionnaire, has been assessed in a sample of 64 patients with chronic respiratory disease undergoing oxygen therapy. The studied properties were internal consistency, test-retest reproducibility and criterion validity. The St George's showed a good internal consistency with Cronbach's alpha coefficients from 0.61 to 0.95 and a good reproducibility with Intraclass Correlation Coefficients (ICC) from 0.67 to 0.95. High correlation with dyspnea (p=0.0004 to 0.01) showed a correct criterion validity. So psychometric properties of the French version of the questionnaire are good. However, its administration caused a few problems, and we advice it to be administered by a trained interviewer in such patients.