Study of pressurised metered dose inhalers for the purpose of standardization of quality attributes characterizing uniformity of dosing

Aim. The purpose was to provide the rationale of test in regard to uniformity of fine particles dose for pressurised metered dose inhalers (pMDIs). Materials and methods. The pMDIs containing suspensions of salbutamol sulfate (SS) or solutions of beclometasone dipropionate (BD) were studied by laser diffraction and high performance liquid chromatography (HPLC). The particle size distribution of SS, the average dose mass and uniformity of dose mass, the average delivered dose and the uniformity of delivered dose, the average fine particles dose and uniformity of fine particles dose were determined. Apparatus A was used for assessment of fine particles dose. Results. The two analytical procedures for the quantitative determination of SS and BD by HPLC were validated in the ranges with low concentrations of these substances. The 5 medicinal products in pMDI dosage form were studied: 3 preparations were with SS and 2 ones contained BD. It was shown that three products with SS were very similar in regard to particle size distribution in containers and the average values of delivered dose were almost the same, but these products were different in the average dose mass and fine particle dose. According to the research results, the expediency of determining the average dose mass and the tests concerning uniformity of dosing of preparations by dose mass and by fine particle dose was substantiated. It was shown that in the case of pMDI the dosing of solutions of BD was more uniform compared to suspensions of SS. The approaches of leading and other pharmacopoeias concerning uniformity of dosing for pMDIs were critically discussed. The expediency of determination of uniformity of fine particle dose at the stage of pharmaceutical development was substantiated, as the therapeutic effect depends on fine particle dose. Issues concerning standardization pMDIs in regard to uniformity of fine particle dose were discussed. Conclusions. The expediency of standardization and quality control of pMDIs in regard to such attributes as the average dose mass, which characterizes the volume of the metering chamber of the valve as well as the uniformity of the dose mass and the uniformity of fine particle dose, which assure the therapeutic effect of each dose of the product was substantiated

Inspiratory flows and the aerosol cloud from dry powder inhalers

The relationship between the delivered dose, the fine particle fraction and the fine particle dose and the value of inspiratory flow generated by the patient is one of the most important features of dry powder inhalers (DPIs). It significantly affects the amount of pulmonary deposition of the inhaled drug and the clinical effect of the drug. The results of research evaluating these relationships for popular in Poland dry powder inhalers are presented. Flow-dependent, relatively flow-dependent and relatively flow-independent inhalers are demonstrated.

Generation of High Dose Inhalable Effervescent Dispersions against Pseudomonas aeruginosa Biofilms

Purpose Novel particle engineering approach was used in this study to generate high dose inhalable effervescent particles with synergistic effects against Pseudomonas aeruginosa biofilms. Methods Spray dried co-amorphous salt of ciprofloxacin (CFX) and tartaric acid (TA) was prepared and coated with external layer of sodium bicarbonate and silica coated silver nanobeads. Design of experiments (DOE) was used to optimize physicochemical properties of particles for enhanced lung deposition. Results Generated particles were co-amorphous CFX/TA showing that CFX lost its zwitterionic form and exhibiting distinct properties to CFX/HCl as assessed by FTIR and thermal analysis. Particles exhibited mass mean aerodynamic diameter (MMAD) of 3.3 μm, emitted dose of 78% and fine particle dose of 85%. Particles were further evaluated via antimicrobial assessment of minimum inhibitory concentrations (MIC) and minimum biofilm eradication concentration (MBEC). MIC and MBEC results showed that the hybrid particles were around 3–5 times more effective when compared to CFX signifying that synergistic effect was achieved. Diffusing wave spectroscopy results showed that the silver containing particles had a disruptive effect on rheological properties as opposed to silver free particles. Conclusions Overall, these results showed the potential to use particle engineering to generate particles that are highly disruptive of bacterial biofilms.

Automated Filling Equipment Allows Increase in the Maximum Dose to Be Filled in the Cyclops® High Dose Dry Powder Inhalation Device While Maintaining Dispersibility

In recent years there has been increasing interest in the pulmonary delivery of high dose dry powder drugs, such as antibiotics. Drugs in this class need to be dosed in doses far over 2.5 mg, and the use of excipients should therefore be minimized. To our knowledge, the effect of the automatic filling of high dose drug formulations on the maximum dose that can be filled in powder inhalers, and on the dispersion behavior of the powder, have not been described so far. In this study, we aimed to investigate these effects after filling with an Omnidose, a vacuum drum filler. Furthermore, the precision and accuracy of the filling process were investigated. Two formulations were used—an isoniazid formulation we reported previously and an amikacin formulation. Both formulations could be precisely and accurately dosed in a vacuum pressure range of 200 to 600 mbar. No change in dispersion was seen after automatic filling. Retention was decreased, with an optimum vacuum pressure range found from 400 to 600 mbar. The nominal dose for amikacin was 57 mg, which resulted in a fine particle dose of 47.26 ± 1.72 mg. The nominal dose for isoniazid could be increased to 150 mg, resulting in a fine particle dose of 107.35 ± 13.52 mg. These findings may contribute to the understanding of the upscaling of high dose dry powder inhalation products.