Aerodynamic deposition of combination dry powder inhaler formulations in vitro: A comparison of three impactors

Taki, Mohammed; Marriott, Christopher; Zeng, Xian-Ming; Martin, Gary P.

doi:10.1016/j.ijpharm.2009.12.031

Cited by 59 publications

(36 citation statements)

References 45 publications

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“…4) Meanwhile, the cut-off diameters were useful to calculate with the relational equation 7) at a T max PIFR of 0.5 s. It was also suggested that FPF for the claimed dose was significantly lower at a flow rate of 40 L/min as compared to 60 L/min, and also tended to be lower at a flow rate of 28 L/min as compared to that of 60 L/min (p=0.06). Thus, PIFR was shown to affect drug deposition in the lung after inhalation with the MF-DPI.…”

Section: Discussionmentioning

confidence: 98%

“…The cut-off diameters for each stage were calculated by substitution of PIFR in the relational equation at various PIFR values. 7) However, it is uncertain whether this equation is reliable, because there is no evidence for a T max PIFR value of 2.5 s. Therefore, the reference cut-off value in the cascade impactor test was used for evaluation of the rate of the doses delivered into the lung and the amount of drug in stages 3 to 7 was assessed at each PIFR. In addition, we used a PIFR of 28.3 L/min for 5 s, which is the reference cascade impactor test.…”

Section: Calculation Of Rate Of Drug Deposition After Inhalation Undementioning

confidence: 99%

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Investigation of Appropriate Inhalation Technique for Mometasone Furoate Dry Powder Inhaler

Yokoyama

Ito

Mihashi

et al. 2016

Biological & Pharmaceutical Bulletin

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The aim of this study was to establish an appropriate inhalation method with a mometasone furoate dry powder inhaler (MF-DPI). Utilizing a tone-based inhalation training device, we investigated the maximum peak inspiratory flow rate time (T max PIFR) and peak inspiratory flow rate (PIFR) to determine whether either had an influence on lung deposition with use of an MF-DPI. A low tone indicated a PIFR of 28 L/min and a high tone that of 40 L/min, while 60 L/min was considered to be the standard. We established an inhalation profile in consideration of a human inhalation pattern, in which T max PIFR was set at 0.5 s (T max PIFR 0.5 s) and 2.5 s (T max PIFR 2.5 s). The reference cut-off value derived with a cascade impactor test was used for evaluation of the rate of delivered dose in the lung, which was the amount of drug from stage 3 to 7 at all PIFRs. We then investigated the relationship of the fine particle fraction (FPF) with the claimed dose at T max PIFR of 0.5 s and PIFR. There were no differences among the T max PIFR values for the doses emitted from the device or for the rate of delivered doses in stages 3-7. However, FPF for the claimed dose at 40 L/min was significantly lower than that at 60 L/min, which was dependent on PIFR. Our results showed that PIFR but not T max PIFR has an effect on lung deposition after inhalation with an MF-DPI.Key words mometasone furoate; dry powder inhaler; maximum peak inspiratory flow rate time; peak inspiratory flow rate; lung deposition A mometasone furoate dry powder inhaler (MF-DPI) is a device utilized for administration of inhaled corticosteroid, which is used for treatment of asthma. MF binds with high affinity to the corticosteroid receptor and has anti-inflammatory potency, [1][2][3] and is formulated for delivery via a breath-actuated DPI using a Twisthaler ® . Doses emitted from the device have been shown to be high, with flow rates ranging from 28.3 to 70 L/min. 4) That study also revealed that the dose emitted from the device has a relationship with flow rate, 4) though the relationship between dose and lung deposition amount is not clear. Furthermore, the mass median aerodynamic diameter (MMAD) of an MF-DPI is 2.0 µm, the smallest among available, thus it is characterized by the design of the particles used, which reach from the central to small airway. An inhalation training device (manufactured by Taisei Kako Co., Ltd.) that emits tones and is used in a manner similar to an MF-DPI has been produced to practice inhalation. This device produces a low tone at a peak inspiratory flow rate (PIFR) of 28 L/ min and a high tone at that of 40 L/min. However, the relationship between PIFR-produced tones and the dose delivered to the lung has not been examined.The rate of drug deposition in the lung has been examined in vitro in inhalation experiments. Those results revealed that PIFR actually sensed by patients was not reflected in those experimental results, as resistance to inhalation was not included in measured PIFR. In addition, individualized inhalation profi...

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Section: Discussionmentioning

confidence: 98%

Section: Calculation Of Rate Of Drug Deposition After Inhalation Undementioning

confidence: 99%

Investigation of Appropriate Inhalation Technique for Mometasone Furoate Dry Powder Inhaler

Yokoyama

Ito

Mihashi

et al. 2016

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

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“…Few high-performance liquid chromatography (HPLC) analytical methods have been published so far for SX and FP simultaneous determination in pharmaceutical formulation [3][4][5][6][7]. According to the International Conference on Harmonization guidelines, if a value for the detection limit is obtained by calculation or extrapolation, this estimate should be subsequently validated by an independent analysis of a suitable number of samples known to be near or at the detection limit which has not been the case so far [8].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the methods with LLOQ above 0.1 μg mL −1 are not suitable for monitoring the invitro deposition pattern. Moreover, in some methods, the quantitation limit had not been provided [6] or only theoretical values of detection limits calculation, based on the standard, were assessed [7]. The methods involving spectrophotometry are widely used in pharmaceutical control laboratories due to their simplicity, low-cost instrumentation, and adaptability.…”

Section: Introductionmentioning

confidence: 99%

HPLC method for simultaneous determination of salmeterol xinafoate and fluticasone propionate for the quality control of dry powder inhalation products

Pączkowska

Smukowska

Tratkiewicz

et al. 2015

Acta Chromatographica

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Summary.A simple and accurate reversed phase high-performance liquid chromatography (HPLC) method has been developed for the estimation of uniformity of dosage units, and delivered dose uniformity tests of fluticasone propionate and salmeterol xinafoate in samples obtained during the fine particle mass determination, using C8 Luna (2) 100A 100 × 4.6 mm, 5 micrometer particle size in gradient mode, with mobile phase comprising of buffer solution: 0.6% trifluoroacetic acid solution in watertetrahydrofurane (8:2 v/v) and acetonitrile-methanol (1:1 v/v) in the ratio of 60:40 v/v. The flow rate was 1.5 mL min −1 , and the detection was monitored by ultraviolet (UV) detector at 239 nm and 250 nm. Linearity was observed in the concentration range of 0.025-4.8 μg mL −1 for salmeterol xinafoate and 0.04-32.5 μg mL −1 for fluticasone propionate (R 2 > 0.999). The recovery in the range from 98.2% to 102.7% and relative standard deviation (RSD) ≤ 2.2% demonstrated accuracy and high precision of the method. The quantification limit at an injection volume of 40 μL was 0.04 μg mL −1 for fluticasone propionate and 0.025 μg mL −1 for salmeterol xinafoate. The developed and validated method can be successfully applied for simultaneous quality control of dry powder inhalation products containing salmeterol xinafoate and fluticasone propionate in pharmaceutical industry.

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“…5) For effective pulmonary deposition after inhalation, in general, the optimal aerodynamic diameter of drug particles is less than 6 µm. 6,7) However, micronized drug particles tend to be highly cohesive and poorly flowable, leading to low-level performance. To solve these problems, it is usual for an excipient, such as coarse lactose monohydrate, to be formulated to physically attach to fine active ingredients.…”

mentioning

confidence: 99%

Safety Evaluation of Dry Powder Formulations by Direct Dispersion onto Air–Liquid Interface Cultured Cell Layer

Asai

Okuda

Yamauchi

et al. 2016

Biological & Pharmaceutical Bulletin

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Most safety evaluations of dry powder inhalers (DPIs) using cultured cells have been performed with dry powder formulations dissolved in a medium. However, this method is not considered to be suitable to evaluate the safety of inhaled dry powder formulations correctly since it cannot reflect the actual phenomenon on the respiratory epithelial surface. In this study, we established a novel in-vitro safety evaluation system suitable for DPIs by combining an air-liquid interface cultured cell layer and a device for dispersing dry powders, and evaluated the safety of candidate excipients of dry powders for inhalation. The safety of excipients (sugars, amino acids, cyclodextrins, and positive controls) in solutions was compared using submerged cell culture systems with a conventional 96-well plate and Transwell ® . The sensitivity of the cells grown in Transwell ® was lower than that of those grown in the 96-well plate. Dry powders were prepared by spray-drying and we evaluated their safety with a novel in-vitro safety evaluation system using an air-liquid interface cultured cell layer. Dry powders decreased the cell viability with doses more than solutions. On the other hand, dissolving the dry powders attenuated their cytotoxicity. This suggested that the novel in-vitro safety evaluation system would be suitable to evaluate the safety of DPIs with high sensitivity.Key words dry powder; safety evaluation; air-liquid interfaced culture; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; A549 cell Pulmonary drug delivery has been investigated as not only a local treatment for respiratory diseases such as asthma or chronic obstructive pulmonary disease, but also as an alternative route for the systemic delivery of macromolecule drugs such as insulin, calcitonin, and heparin. 1-4)Among the three major systems for pulmonary deliverynebulizers, pressurized metered-dose inhalers (pMDIs), and dry powder inhalers (DPIs)-DPIs have several advantages, including favorable portability, a low cost, and the lack of a need for propellants. Furthermore, the handling of DPIs is easier than that of pMDIs because of breath-actuated passive aerosolization. 5)For effective pulmonary deposition after inhalation, in general, the optimal aerodynamic diameter of drug particles is less than 6 µm.6,7) However, micronized drug particles tend to be highly cohesive and poorly flowable, leading to low-level performance. To solve these problems, it is usual for an excipient, such as coarse lactose monohydrate, to be formulated to physically attach to fine active ingredients. 8,9) It has been recently reported that the addition of amino acids or cyclodextrins (CyDs) as excipients improves pulmonary delivery. 10,11) As for fundamental research on DPIs, evaluation of the physical properties such as particle size and pulmonary deposition is mainstream, whereas biological evaluation such as of the efficacy and safety is essential for clinical application. 12)These biological evaluations of dry powder formulations are often conduct...

show abstract

Aerodynamic deposition of combination dry powder inhaler formulations in vitro: A comparison of three impactors

Cited by 59 publications

References 45 publications

Investigation of Appropriate Inhalation Technique for Mometasone Furoate Dry Powder Inhaler

Investigation of Appropriate Inhalation Technique for Mometasone Furoate Dry Powder Inhaler

HPLC method for simultaneous determination of salmeterol xinafoate and fluticasone propionate for the quality control of dry powder inhalation products

Safety Evaluation of Dry Powder Formulations by Direct Dispersion onto Air–Liquid Interface Cultured Cell Layer

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