State of the Art in Capsule-Based Dry Powder Inhalers: Deagglomeration Techniques and the Consequences for Formulation Aerosolization

Dry powder inhalers (DPIs) are widely used for the therapy of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), or bacterial infections. To achieve a sufficient therapeutic effect by deposition of the powder in the lower respiratory tract, the powder particles should have an aerodynamic diameter of <5 µm. For this purpose, special manufacturing processes such as jet-milling of the active pharmaceutical ingredient (API) are used in the pharmaceutical industry to produce micronized particles in the inhalable size range. However, increasing the total particle surface area by this technology often results in very cohesive particles that have poor aerosolization efficiency and flowability. To overcome this problem and produce flowable and deagglomerable powder formulations, various formulation techniques are used, such as mixing the jet-milled particles with large carrier particles (e.g., lactose) to form interactive blends. This method of formulation is preferred in the pharmaceutical industry due to the resulting high storage stability of the crystalline APIs. In the case of particle engineered approaches, such as spray-dried particle formulations, the device should overcome the cohesive particle interactions during inhalation. Apart from the formulation’s characteristics, it is known that the success of therapy with passive breath-actuated DPIs depends mainly on the physiological conditions of the patient and the inhalation profiles generated. Inhalation performed with insufficient respiratory force and duration results in an unintentionally low emitted dose with insufficient powder deagglomeration and thus insufficient therapeutic success]. Since a COPD patient cannot achieve the same inspirational flow profile as a healthy person, this leads to decreased deposition of the powder in the lungs. To counteract this problem, high intrinsic resistance devices are being developed that should deliver the same amount of aerosol regardless of airway resistance and applied inhalation flow rate. In addition to the aforementioned inhalation properties of the patient, the delivered powder fraction and the resulting aerodynamic properties of the aerosol are also related to the device properties, which include the opening mechanism of the capsule being used, the movement of the capsule (vibration, rotation, shaking), and the interaction between the powder, the capsule, and the inhaler wall. The size and position of the holes pierced in the capsule also influence the aerosol properties .

Since the success of inhalation depends on many factors, as described, marketed delivery systems are designed as combination products consisting of the formulation and the DPI to minimize the number of potential sources of error. The formulation and the device are designed to work together to achieve a satisfactory therapeutic effect. This results in a marketed formulation being prescribed by the physician only with the inhaler intended for it and patients having to relearn how to use a different inhaler when they change medications, which could affect treatment adherence]. Since different inhalers result in different deagglomeration of the same powder, developing and marketing a generic device is challenging.

To investigate what the current market looks like, the study compared three capsule-based DPIs. Due to geometry and airflow, each unit has a different capsule motion and consequently a different mechanism for deagglomerating the powder. The study was designed to show which deagglomeration unit provides the highest fine particle fraction (FPF_TD/EF = fraction of particles with an aerodynamic diameter < 5 µm of the total dose/emitted fraction) regardless of the formulation tested and actuation conditions used. To determine the influence of capsule movement on powder ejection and the number of particles that can potentially reach the lungs, devices with axial capsule vibration (Handihaler^® (Boehringer Ingelheim, Ingelheim am Rhein, Germany)), capsule rotation (Lupihaler^® (Lupin Limited, Mumbai, India)) = RS01 equivalent device), and oscillating capsule movement (Presspart prototype DPI = PP-DPI) were compared (Figure 1). While the Handihaler^® and Lupihaler^® DPI are marketed devices that are well-known and extensively described, the Presspart prototype DPI is a novel capsule-based device. In order to analyze the “applicability of the devices for different formulations”, a series of drug formulations developed with different formulation techniques were tested. While the marketed formulation Cyclocaps^® (PB Pharma GmbH, Meerbusch, Germany) is an interactive blend of micronized albuterol sulfate and alpha lactose monohydrate, a spray-dried rifampicin formulation was also tested. To demonstrate the potential use of carrier particles for spray-dried API particles, a spray-dried batch of amoxicillin was mixed with Inhalac 251^® (MEGGLE GmbH & Co. KG, Wasserburg am Inn, Germany) (ratio 1:24) in a further step to form a binary mixture, which was aerosolized using the above inhalers. To demonstrate the potentially flow-profile-independent deagglomeration behavior of the selected DPIs for the tested formulations, 50 L/min was selected as the low flow rate and 100 L/min as the high flow rate. These settings were also chosen because they closely approximate the actual flow rates of the low (Lupihaler) or high intrinsic resistance (PP-DPI, Handihaler) devices used in this study at a pressure drop of 4. To analyze the deagglomeration behavior of the devices for each formulation, in addition to the relative powder deposition in each stage, the FPF_TD/EF was compared.