(M0930-04-20) Comparative Study of Capsule-Based DPIs for Drug Detachment from Carrier Particles in Interactive Blends

Purpose: Dry powder inhalers (DPIs) are used for the therapy of lung diseases. The powder particles should have an aerodynamic diameter of < 5 µm to achieve a sufficient therapeutic effect by deposition in the lower airways. Since the success of inhalation depends on many factors, commercially available delivery systems are usually DPIs in fixed combination with the intended formulation, which is usually an interactive mixture, and changing the drug often forces the patient to use a different device, which requires relearning how to use it, resulting in lower adherence and inadequate therapy [1]. To investigate whether DPIs can achieve successful results for binary blends not designed for the DPI in question by detaching the drug from the carrier particles regardless of the flow rate used, three capsule-based DPIs were compared in vitro for their deagglomeration behavior for a commercial albuterol sulfate-lactose mixture used as a surrogate for binary blend formulations. Due to the geometry of the device and the airflow within the DPI during actuation, each unit has a different capsule movement and consequently a different mechanism for deagglomeration of the powder. The study was designed to show which deagglomeration unit provides the highest FPF regardless of the actuation conditions used. To determine the influence of capsule movement on powder output and the amount of particles that can potentially enter the lungs, devices with rotating capsule movement (Lupihaler^®), axial capsule vibration (Handihaler^®) and oscillating capsule movement (Novel DPI) were compared (fig. 1) [2, 3].

Methods: Materials - A commercial available formulation of albuterol sulfate–alpha lactose monohydrate (Cyclocaps^®) was purchased from a pharmacy. While the marketed devices Lupihaler^® and Handihaler^® were purchased from a pharmacy, a novel DPI was also tested.

Test procedure for the aerosol classification with the Next Generation Impactor - A Next Generation Impactor (NGI) (Copley Scientific Limited, Nottingham, United Kingdom) was used to characterize the aerosol properties of the formulation using the different devices. Prior to the experiments, each cup was coated with a 1 % glycerol-methanol (m/v) solution and 15 mL of the diluent was placed in the preseparator unit. After actuating, the particles were dissolved from each stage using a water-methanol mixture (1:1 % v/v). Flow rates of 50 and 100 L/min and an actuation volume of 4 liters were used. All experiments were performed in triplicate.

High-performance liquid chromatography analysis - Quantification of the API was performed by high-performance liquid chromatography analysis (Shimadzu, LC-2030C 3D Plus, Kyoto, Japan) using an RP18 column (Lichrospher 100 RP 18-5µ EC, 250 x 4.6 mm). The photodiode array detector was set to a wavelength of 275 nm. An isocratic flow of 1.4 mL/min of a mixture of a phosphate buffer pH 3/methanol (80:20 v/v (%)) was used and a column temperature of 40°C was set.

Data processing - The NGI plots show the relative powder deposition on the different stages. The error bars indicate one standard deviation. The fine particle fraction (FPF_TD/EF (fraction of particles with an aerodynamic diameter < 5 µm of the total dose/emitted fraction)) was calculated as described in USP < 601 > [4].

Results: Testing of the albuterol sulfate formulation at 50 L/min resulted in high powder deposition in the preseparator for each device (fig. 2). Regardless of the DPI actuated, a higher flow rate resulted in less powder deposition in the device, while powder retention in the capsule was not affected by the different flow rates. The lower powder deposition in the induction port (IP) after using the novel DPI, as well as the lower powder retention in the Handihaler, resulted in a higher FPF than with the Lupihaler. While at 50 L/min the powder deposition in the preseparator was similar for all DPIs used, actuation of the novel DPI at 100 L/min resulted in lower deposition in the preseparator compared to the other two devices (fig. 3).

Conclusion: From this study, it can be concluded that progress is generally being made in the development of deagglomeration concepts for capsule-based DPIs for the aerosolization of binary blends. With regard to the design of the novel DPI, it has been shown that the oscillating motion of the capsule can result in less powder retention in the capsule than the rotating motion. Comparison of the results of this formulation showed that a lower amount of active ingredient was found in the IP and in the preseparator for the novel DPI independent of the flow rate applied, indicating a better deagglomeration behavior and a better detachment of the active ingredient from the carrier particles. Comparing the FPF, the novel DPI achieved the highest FPF regardless of the flow rate applied, highlighting the functionality of the deagglomeration mechanism for this binary blend.

References: 1. Atkins PJ. Dry Powder Inhalers: An Overview. Respir CARE. 2005;50(10):9.
2. Martinelli F, Balducci AG, Rossi A, Sonvico F, Colombo P, Buttini F. “Pierce and inhale” design in capsule based dry powder inhalers: Effect of capsule piercing and motion on aerodynamic performance of drugs. Int J Pharm. 2015 Jun;487(1–2):197–204.
3. Shur J, Lee S, Adams W, Lionberger R, Tibbatts J, Price R. Effect of Device Design on the In Vitro Performance and Comparability for Capsule-Based Dry Powder Inhalers. AAPS J. 2012 Dec;14(4):667–76.
4. AEROSOLS, NASAL SPRAYS, METERED-DOSE INHALERS, AND DRY POWDER INHALERS. 2012;22.

Acknowledgements:

Funding: This research was funded by the Federal Ministry for Economic Affairs and Energy (BMWi, Germany) (EIDEG project, Grant reference: 03ET1489A - D).

Conflicts of Interest: This research topic was partially sponsored by Presspart GmbH & Co. KG. The company had no role in the design of the study, in the collection, analyses or interpretation of the data. The other authors declare no conflict of interest.


Fig. 1: Schematic representation of the DPIs


Fig. 2: NGI results of the albuterol sulfate formulation actuated with different DPIs at 50 L/min (*p < 0.05, one-way ANOVA)


Fig. 3: NGI results of the albuterol sulfate formulation actuated with different DPIs at 100 L/min (*p < 0.05, one-way ANOVA)