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Tobramycin is an aminoglycoside antimicrobial drug frequently used in anti-pseudomonal therapy in cystic fibrosis and non-cystic fibrosis bronchiectasis patients. Therapeutic drug monitoring is routinely performed to increase efficacy and reduce the chance of toxicity. The most frequently used method to quantify tobramycin in serum or plasma is with an immunoassay method. However, immunoassays lack sensitivity to evaluate the lower concentrations of tobramycin for pharmacokinetic studies of for instance inhaled tobramycin. The aim of this study was to optimise the Syva® Emit® 2000 Tobramycin Assay combined with the ARCHITECT c8000. This adapted method was validated for accuracy and precision, having within-run, between-run variation. The adapted tobramycin immunoassay method has a linear range of 0.03 to 0.6 mg/L, which is comparable to liquid chromatography-mass spectrometry methods. The immunoassay method was validated with representative samples and has been implemented in routine analysis.

Inhaled antibiotics have been a valuable tool in treating pulmonary infections in cystic fibrosis patients for decades, and the pulmonary route is now becoming increasingly interesting for other infectious diseases like tuberculosis too. Especially with multidrug and extensively drug-resistant tuberculosis emerging, great effort is put into the improvement of pulmonary antibiotic administration to fight this global threat. Several reviews have been written on inhalable antibiotics, giving clear overviews of the compounds of interest. Furthermore, various formulation studies and administration strategies are on-going with these compounds. What is often missing is a critical evaluation of these developments. Several risks may be involved varying from obtaining insufficient local drug concentrations to adverse side effects and unwanted changes in physiological processes from the excipients used. In this manuscript, the pros and cons and feasibility of recent advances in pulmonary antibiotic tuberculosis therapy are presented and critically evaluated. Furthermore, the advantages of dry powder inhalation over wet nebulisation for inhaled antibiotics in developing countries where prevalence of tuberculosis is highest are discussed. It has to be concluded that a greater effort in good inhaler development and more research in the physicochemical properties of the compounds of interest are needed. (C) 2013 Elsevier B.V. All rights reserved.

Background: patients prefer dry powder inhalation to nebulisation but the Colobreathe dry powder inhaler for colistimethate sodium (CMS) is not well appreciated in the Netherlands for a number of different reasons, including serious cough problems by some patients after inhalation of the drug. Aim: to assess the suitability of the Twincer as alternative to the Colobreathe for patients having problems with this capsule based inhaler. Methods: in vitro evaluation of the Twincer (55 mg) and Colobreathe (125 mg) was performed using the Next Generation Impactor and a laser diffraction apparatus (Sympatec HELOS) operated at 4 kPa (inhalation volume: 4L; n = 3). Results: laser diffraction analyses shows a finer aerosol from the Twincer than from the Colobreathe. Delivered CMS doses and fine particle doses (FPFs 1-5 µm) from Colobreathe were 126 mg (+14.7/-31.9 mg) and 25.5 mg (+2.8/-3.5 mg) respectively versus 48.5 mg (+2.9/-3.3 mg) and 26.4 mg (+1.4/-1.2 mg) from Twincer. Capsule fragmentation and emission of capsule fragments was observed during evaluation of the Colobreathe but not for the Twincer (having the drug in an aluminum blister). Conclusions: The higher dispersion efficiency of the Twincer (FPF is 54.4% of delivered dose versus 20.2% for Colobreathe) enables to inhale a much lower dose (at lower flow rate) without capsule fragments in the aerosol. As a consequence, the Twincer is expected to be better tolerated by patients and, therefore, provides a suitable alternative to the Colobreathe. This expectation is corroborated by positive feedback from the first patients suffering from CF or non-CF bronchiectasis who received the Twincer on the basis of 9medical need9.

Bronchiectasis patients infected with P. aeruginosa require adequate treatment with antibiotics. The primary objectives of this study were to assess local tolerability and the pharmacokinetic parameters of inhaled excipient free dry powder tobramycin free base in this patient group. Escalating doses were administered with a new DPI (Cyclops) to eight participants with non-cystic fibrosis bronchiectasis who were trained in operating the inhaler correctly. During drug administration the inspiratory flow curve was recorded and several flow parameters were computed. Local tolerability was assessed by spirometry and recording adverse events. Pharmacokinetic parameters were computed from serum samples collected before, and 15, 30, 45, 60, 75, 90, 105, 120 min; 4, 8 and 12 h after inhalation. The free base of tobramycin was well tolerated and a good drug dose-serum concentration correlation was obtained. Relatively small inhaled volumes were computed from the recorded flow curves, resulting presumably in substantial deposition in the central airways – i.e., at the primary site of inflammation. Normalised maximum serum concentration (C max ) increased with decreasing inhaled volume. We believe that this can be explained with an increased bronchial circulation in bronchiectasis patients from 1% to 30% of the cardiac output due to the inflammation. Because bronchiectasis is progressively deteriorating, accompanied by increased inflammation, it can be hypothesised that the higher blood circulation at a higher degree of inflammation increases the absorption rate of tobramycin from the site of deposition. Our data challenge to further investigate the effect of increased inflammation on the C max .

Patients infected with pathogenic bacteria have to be treated with antibiotics. When the infection is in the lungs, as for instance in cystic fibrosis, bronchiectasis and tuberculosis, inhaled antibiotics have certain advantages over systemically administered antibiotics. In this study, it is shown that re-designing the Twincer™ high dose disposable inhaler into a device named Cyclops enables effective dispersion of up to 50mg of pure spray dried tobramycin. This proves that spray dried tobramycin powders in the preferred size range for inhalation can be administered without applying complex particle engineering techniques and/or using excipients. Only some coarse sweeper crystals added separately are desired to minimise the inhaler losses to less than 20% at 4 kPa. The fine particle fractions

Dry powder formulations for inhalation have to be screened in animal studies for therapeutic efficacy and safety aspects and both are significantly affected by the dose and the particle size distribution (PSD) of the aerosol that is given. One of the most frequently used apparatus for pulmonary delivery of dry powder formulations in mice studies is the PennCentury (TM) DP-4M Dry Powder Insufflator. To make researchers of future preclinical animal studies with the DP-4M insufflator aware of the pitfalls regarding the conclusions to be drawn from their data, we investigated the dispersion behaviour by the DP-4M insufflator using two to three different powder preparation techniques for four different compounds. The primary PSDs of the different formulations were determined in duplicate by laser diffraction analysis. To measure the PSDs of the aerosols obtained with the DP-4M insufflator, the same diffractometer was used in combination with an in-house constructed adapter for the insufflator. The dispersion efficiency and delivered dose were highly affected by the amount of air available for dispersion; the 200 mu L of air recommended for the type of insufflator used was insufficient for adequate dispersion. In contrast, the weighed dose did not have a profound effect on the dispersion behaviour and the delivered dose of the DP-4M insufflator. Also the physico-chemical powder properties and the applied particle preparation technique influenced the amount and PSD of the delivered aerosol only to a limited extend, with a few exceptions. We advise researchers to investigate the dispersion efficiency and delivered dose from the DP-4M insufflator with the formulation under investigation prior to in vivo studies and it may be necessary to optimise the formulation for administration to mice. (C) 2014 Elsevier B.V. All rights reserved.

In the 50 years following the introduction of the first dry powder inhaler to the market, several developments have occurred. Multiple-unit dose and multi-dose devices have been introduced, but first generation capsule inhalers are still widely used for new formulations. Many new particle engineering techniques have been developed and considerable effort has been put in understanding the mechanisms that control particle interaction and powder dispersion during inhalation. Yet, several misconceptions about optimal inhaler performance manage to survive in modern literature. It is, for example still widely believed that a flow rate independent fine particle fraction contributes to an inhalation performance independent therapy, that dry powder inhalers perform best at 4 kPa (or 60 L/min) and that a high resistance device cannot be operated correctly by patients with reduced lung function. Nevertheless, there seems to be a great future for dry powder inhalation. Many new areas of interest for dry powder inhalation are explored and with the assistance of new techniques like computational fluid dynamics and emerging particle engineering technologies, this is likely to result in a new generation of inhaler devices and formulations, that will enable the introduction of new therapies based on inhaled medicines. © 2014.