RESUMEN

Ipratropium bromide (IPR) and fenoterol hydrobromide (FEN) have recently been combined in a promising inhaler to treat two prevalent inflammatory illnesses of the airways: bronchial asthma and chronic obstructive pulmonary disease (COPD). The necessity for a single, sensitive, and trustworthy analytical approach to cover the diverse and necessary tests of in-vitro and in-vivo studies is greatly grown with the rising production of new fixed combinations. Two novel, selective and environmentally friendly LC techniques were developed in order to guarantee precise measurement of IPR and FEN in their challenging formulation. The initial technique involved high-performance thin-layer chromatography (HPTLC) in conjunction with densitometric quantification. Chromatographic separation was attained on HPTLC plates utilizing ethyl acetate - ethanol - acetic acid (5.0:5.0:0.1, by volume) as a developing system. Densitometric quantification of the separated bands was carried out at 220.0 nm over concentration ranges of 0.50-15.0 µg/band for IPR and 0.50-12.0 µg/band for FEN. High-performance liquid chromatography (HPLC) paired with diode array detection (DAD) was the core of the second technique. The optimized separation was achieved on a Zorbax SB C18 (150 × 4.6 mm, 5 µm) column with a combination of 10.0 mM potassium dihydrogen orthophosphate, pH 5.0 ± 0.1, adjusted with o-phosphoric acid and methanol (70:30, v/v) as the mobile phase and pumped at flow rate of 1.0 mL/min. The peaks were monitored at 220.0 nm using diode array detection, achieving linearity range of 5.0-200.0 µg/mL for both drugs. The ICH criteria have been verified and both methods have been confirmed to be valid, and successfully applied for assay the cited drugs in the Atrovent® comp HFA metered dose inhaler as well as delivered dose uniformity testing of the final product. Finally, whiteness appraisal and several state-of-the-art green evaluation metrics were applied to evaluate the sustainability of the proposed methods. The suggested approaches produced promising results and are the first simple and sustainable methodologies for the simultaneous quantification of both drugs in different real samples, all of which strongly suggest their application in quality control laboratories.

RESUMEN

The present investigation is to study the effect of two different induction ports (IP), i.e., USP IP and USP-modified IP equipped with andersen cascade impactor on in vitro aerodynamic performance along with the impact of USP-modified glass sampling apparatus on delivered dose uniformity of fluticasone propionate (FP) dry powder inhaler (DPI). FP DPI was fabricated by spray drying technique using engineered mannitol microparticles (EMP) with different force controlling agents, i.e., leucine and magnesium stearate. Additionally, commercially available two DPI inhaler devices namely Handihaler® and Breezhaler® were used to aerosolize the FP blends. Spherical smooth surface of EMP showed good powder flow properties and acceptable percentage content uniformity (> 95%). Amounts of FP deposited in cascade assembly using USP-modified IP with the Breezhaler® device was significantly higher (1.32-fold) as compared with the Handihaler® device. Moreover, USP-modified IP showed better deposition as compared with USP IP. Additionally, both inhaler devices showed a satisfactory delivered dose (> 105%) for FP using modified glass sampling apparatus at a flow rate of 60 L/min for 2 s. It was interesting to note that not only formulation properties but also IP geometry and device resistance have significant impact on DPI deposition pattern. This study is a first detailed account of aerodynamic performance of FP using USP-modified IP and USP-modified glass sampling apparatus. Thus, it can be of potential importance for both the academic and industry perspective.

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RESUMEN

The delivered dose uniformity is one of the most critical requirements for dry powder inhaler (DPI) and metered dose inhaler products. In 1999, the Food and Drug Administration (FDA) issued a Draft Guidance entitled Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products-Chemistry, Manufacturing and Controls Documentation and recommended a two-tier acceptance sampling plan that is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity (USP34<601>). This sampling acceptance plan is also applied to metered dose inhaler (MDI) and DPI drug products in general. The FDA Draft Guidance method is shown to have a near-zero probability of acceptance at the second tier. In 2000, under the request of The International Pharmaceutical Aerosol Consortium, the FDA developed a two-tier sampling acceptance plan based on two one-sided tolerance intervals (TOSTIs) for a small sample. The procedure was presented in the 2005 Advisory Committee Meeting of Pharmaceutical Science and later published in the Journal of Biopharmaceutical Statistics (Tsong et al., 2008). This proposed procedure controls the probability of the product delivering below a pre-specified effective dose and the probability of the product delivering over a pre-specified safety dose. In this article, we further propose an extension of the TOSTI procedure to single-tier procedure with any number of canisters.

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