Inhaled dry powder liposomal azithromycin for treatment of chronic lower respiratory tract infection.

A dry powder inhaled liposomal azithromycin formulation was developed for the treatment of chronic respiratory diseases such as cystic fibrosis and bronchiectasis. Key properties including liposome size, charge and encapsulation efficiency powder size, shape, glass transition temperature (Tg), water content and in vitro respiratory deposition were determined. Antimicrobial activity against cystic fibrosis (CF) respiratory pathogens was determined by MIC, MBC and biofilm assays. Cytotoxicity and cellular uptake studies were performed using A549 cells. The average liposome size was 105 nm, charge was 55 mV and encapsulation efficiency was 75 %. The mean powder particle size d[v,50] of 4.54 µm and Mass Median Aerodynamic Diameter (MMAD) was 5.23 µm with a mean Tg of 76˚C and water content of 2.1 %. These excellent physicochemical characteristics were maintained over one year. Liposomal loaded azithromycin demonstrated enhanced activity against P. aeruginosa clinical isolates grown in biofilm. The formulation was rapidly delivered into bacterial cells with > 75 % uptake in 1 h. Rapid uptake into A549 cells via a cholesterol-dependent endocytosis pathway with no cytotoxic effects apparent. These data demonstrate that this formulation could offer benefits over current treatment regimens for people with chronic respiratory infection.

Relative bioavailability of terbutaline to the lung following inhalation, using urinary excretion.

AIMS: The aim of the study was to determine the relative lung and systemic bioavailability of terbutaline. METHODS: On separate days healthy volunteers received 500 µg terbutaline study doses either inhaled from a metered dose inhaler or swallowed as a solution with and without oral charcoal. Urine samples were provided at timed intervals post dosing. RESULTS: Mean (SD) urinary terbutaline 0.5 h post inhalation, in 12 volunteers, with (IC) and without (I) oral charcoal and oral (O) dosing was 7.4 (2.2), 6.5 (2.1) and 0.2 (0.2) µg. I and IC were similar and both significantly greater than O (P<0.001). Urinary 24 h terbutaline post I was similar to IC + O. The method was linear and reproducible, similar to that of the urinary salbutamol method. CONCLUSIONS: The urinary salbutamol pharmacokinetic method post inhalation applies to terbutaline. Terbutaline study doses can replace routine salbutamol during these studies when patients are studied.

Can all patients with COPD use the correct inhalation flow with all inhalers and does training help?

The inhalation rate is important when patients use an inhaler. Dry powder inhalers (DPIs) require an inhalation rate >30 L min(-1) whereas metered dose inhalers (MDIs) should be used at <90 L min(-1). Within the setting of a routine clinic, we have measured peak inhalation flows (PIF) of COPD patients when they used a Diskus (SDSK), Turbuhaler (STBH), Handihaler (SHAND) and MDI. Subjects were then randomised into trained (VT) and non-trained (NT) groups. One hundred and sixty-three patients with a mean (S.D.) age and % predicted FEV(1) of 72.5 (9.9) years and 47.8 (22.2)% completed the study. Of the patients, 4.9%, 14.2% and 57.0% inhaled <30 L min(-1) through SDSK, STHB and SHAND, respectively and 59.5% inhaled >90 L min(-1) with the MDI. Generally, the more severe the COPD, the slower was their PIF with all inhalers. The MDI PIF values in the VT group (n=84) post-training were significantly (p<0.001) slower but there was no change for the DPIs. Of the 55 VT patients inhaling >90 L min(-1) through the MDI only 7 (p<0.001) inhaled too fast post-training. Pre-training 3, 15 and 46 VT subjects inhaled <30 L min(-1) through the SDSK, STBH and SHAND and after training none, 5 and 26 did not inhale faster than this minimum required rate. Some COPD patients have problems achieving required PIFs through DPIs but training is useful to help some exceed the minimum required rate despite only small improvements. The patients found it easier to slow their PIF through the MDI.

Emitted dose estimates from Seretide Diskus and Symbicort Turbuhaler following inhalation by severe asthmatics.

The dose emitted from dry powder inhalers may be inhalation flow-dependent. Using an ex vivo method, the Electronic Lung, we have measured the aerodynamic characteristics of the emitted dose for both active constituents from Seretide Diskus (salmeterol xinafoate 50 mcg; fluticasone propionate 500 mcg) and Symbicort Turbuhaler (formoterol 6 mcg; budesonide 200 mcg). Electronic inhalation profiles were collected from 20 severe asthmatics (mean PEFR 53% predicted) when they inhaled using a placebo Seretide Diskus and a placebo Symbicort Turbuhaler. These were replayed in the Electronic Lung with the respective active inhaler in situ. Mean(S.D.) peak inhalation flow rates (PIFR) through the Diskus and Turbuhaler were 94.7(32.9) and 76.8(26.2) l min(-1), respectively. From the Electronic Lung the Diskus inhalation profiles provided a mean(S.D.) fine particle dose (FPD) for fluticasone propionate and salmeterol of 20.4(4.8) and 18.4(4.4)% labelled dose. For Turbuhaler inhalation profiles the FPD was 23.1(12.9) and 20.7(11.1)% labelled dose for budesonide and formoterol, respectively. The linear (p < 0.001) relationships between FPD against PIFR for budesonide and formoterol were 3 (p = 0.002) and 2.8 (p = 0.007) times steeper than fluticasone propionate and salmeterol, respectively. The results highlight a more significant effect of inspiratory flow on variable dosage emission when using the Symbicort Turbuhaler compared with the Seretide Diskus.

Aerodynamic dose emission characteristics of dry powder inhalers using an Andersen Cascade Impactor with a mixing inlet: the influence of flow and volume.

An interaction between device resistance and inhalation flow provides the 'energy' to de-aggregate the metered dose of dry powder inhalers (DPIs). Hence all dry powder inhalers demonstrate flow dependent dose emission but information on this at low flows is not available. We have adapted the compendial method for the Andersen Cascade Impactor (ACI) to include a mixing inlet to determine the aerodynamic dose emission characteristics of a salbutamol Diskus(®) [DSK], Easyhaler(®) [EASY] and Clickhaler(®) [CLICK] and the terbutaline Turbuhaler(®) [TBH] using flows of 10-60 L/min and inhalation volumes of 2 and 4 L. All DPIs demonstrated flow dependent dose emission (p<0.001) but there was no difference in the measurements between 2 and 4 L. The flow dependent dose emission properties of each DPI started to plateau when the pressure change inside each device, during an inhalation, was between 1 and 1.5 kPa. This corresponds to inhalation flows of 40.1-49.1, 25.4-28.9, 23.6-28.9 and 29.7-36.3 L/min through DSK, CLICK, EASY and TBH. The adapted methodology allows measurements at low flows. The results highlight that the compendial methodology to use an inhaled volume of 4 L with the ACI could be replaced by 2 L and that the recommendation to make measurements using a pressure drop of 4kPa should be revised.

Aerodynamic characteristics of a dry powder inhaler at low inhalation flows using a mixing inlet with an Andersen Cascade Impactor.

The aerodynamic characteristics of the dose emitted from a dry powder inhaler (DPI) are inhalation flow dependent but have not been determined for low flows. We have designed novel methodology to measure these at <28.3 lmin(-1). The original Andersen Cascade Impactor (ACI) designed for use at 60 lmin(-1) was adapted to include a mixing inlet (MIXINLET) which allows inhalation flows through the DPI from 5 to 60 lmin(-1). The mean fine particle dose (FPD) from a formoterol Turbuhaler using the MIXINLET method at 10, 20, 28.3, 40 and 60 lmin(-1) was 0.55, 1.39, 1.80, 2.88 and 5.86 microg and the mass median aerodynamic diameter (MMAD) was 6.6, 6.0, 5.4, 5.1 and 2.8 microm. Similarly, the FPD using the ACI method was 0.13, 0.69, 1.50, 2.48 and 5.42 microg and MMADs were 12.2, 7.4, 5.5, 4.8 and 2.7 microm. The accuracy of the original ACI <28.3 lmin(-1) is unknown. The ACI with the mixing inlet allows the determination of the in vitro dose emission properties of DPIs at flows <28.3 lmin(-1) whilst maintaining a constant flow through the ACI. This methodology, therefore, can help to focus attention to the lowest inhalation flow required for a DPI.