Abstract
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
Highlights
The main regulatory and guidance documents, which outline the requirements for the quality of pressurized metered dose inhalers, are the European Pharmacopoeia [1], in particular, the general articles “Preparations for inhalation”, “Pressurized pharmaceutical preparations” and “2.9.18
The delivered dose (DD) is the quantity of an active substance that is available to the user, exdevice, on a per dose basis; this dose is the part of the metered dose except for that part which has deposited on the actuator
It was shown that for the three pressurised metered dose inhalers (pMDIs) with salbutamol sulfate (SS) the particle size distribution in the containers and the average delivered dose were almost the same, but these preparations were different in the average dose mass and fine particle dose
Summary
The main regulatory and guidance documents, which outline the requirements for the quality of pressurized metered dose inhalers (pMDI), are the European Pharmacopoeia [1], in particular, the general articles “Preparations for inhalation”, “Pressurized pharmaceutical preparations” and “2.9.18. “Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products” [2]. Аccording to these documents several types of dose can be distinguished for pMDI. The fine particle dose (FPD) is the part of delivered dose that is consisted from small particles of an active substance (≤ 5 μm) that are capable to penetrate into the lung during inhalation and provide therapeutic effect. The other part of delivered dose contains larger particles of an active substance that deposit in the mouth and throat of the patient and do not provide therapeutic effect [7, 8]. The small and larger particles contained in these two parts of delivered dose settle on different stag-
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