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Puncture and aerosolization tests measure the effectiveness of hard-shell capsules used in dry powder inhalers (DPIs) for inhaled drug products.
Dry powder inhalers (DPIs) are one of the types of devices used to deliver orally inhaled drug products. In a DPI, the drug is encapsulated in a hard-shell capsule and released by the device at the time of use. “The attraction of using a capsule-based DPI is its simplicity. The powder formulation consists of solely the API, or a mixture of API with a carrier particle, such as lactose or mannitol,” notes Justin Kalafat, ACG North America scientific business development manager. Although DPIs have primarily been used for treating respiratory diseases, such as asthma or chronic obstructive pulmonary disease, pharmaceutical companies are now also considering inhalation delivery methods as alternatives to oral or parenteral delivery for other drug products as well. Pharmaceutical Technology spoke with Kalafat and with Fernando Diez, ACG Europe scientific business development manager, about the requirements for capsules used in DPIs and the methods used to test their performance.
PharmTech: What are the key requirements for capsules used for dry powder inhalers?
ACG: The two key requirements of capsules used in DPIs are puncturing and aerosolization. For hard-shell capsules to function effectively as drug reservoirs in DPIs, the capsule must be punctured with sharpened pins or cut with blades to release the powdered medication upon inspiration. During this process, the capsule cannot shed pieces or create hindrances to the outflow of the powder. For example, if a pin punctures the capsule and a flap is produced, it must stay attached and remain open. A closure of the flap would result in an obstruction of the opening, hindering the powder’s delivery to the patient. Additionally, if the capsule cracks or shatters during puncturing, the fragmented pieces can interfere with the medication passing though the device’s filter as inhaled by the patient.
Aerosolization is the process of converting a physical substance into the form of small, light particles, to be carried on the air. In this process, the capsule enables the powder release (i.e., emitted dose). It must not make agglomerates that increase powder particle size; higher moisture content of a capsule material tends to increase agglomerate creation in API through capillary action.
In inhalation technology, particle size matters. To reach the peripheral airways, where the drug is most efficiently absorbed, particles need to be optimized in the 1–5 µm aerodynamic diameter range. The efficiency of the aerosolization process is measured using the fine particle fraction (FPF), defined as the percentage of emitted dose with particles in the targeted 1–5 µm diameter range.
PharmTech: What tests need to be performed to determine these properties?
ACG: In a puncture test, the force and deformation profile of a pin moving onto a capsule wall at different relative humidities is registered. Puncturing performance can be described by two values taken from these profiles: puncturing force (maximum force registered) and capsule deformation (displacement at maximal force). It is also important to measure the puncturing area and shape, as this defines the space through which the drug leaves the capsule. Small areas and irregular shapes can lead to non-reproducible emitted doses to the patient.
As for aerosolization, a device with a capsule is attached to a next-generation cascade impactor (NGI) operating at a flow rate (normally 60 L/m) for a specific interval (normally four seconds). Drug deposition on various parts of the NGI equipment and the device is measured, and the emitted dose and FPF are calculated.
ACG presented a paper at AAPS 2017 in San Diego, CA about optimizing the inhalation capsule puncturing process by using a design of experiments. In this work, four factors were considered: capsule type, temperature, relative humidity, and device actuation. The experiments showed that the force necessary to open the capsules is highly reproducible and that hydroxypropyl methylcellulose capsules show lower force than gelatin. New research data will be submitted at the Respiratory Drug Delivery (RDD) 2018 conference in Tucson, AZ, about the reproducibility of the capsule puncturing process. In this study, forces and displacement were measured for different types of capsules (opaque, transparent) and different puncturing sites (cap and body).
PharmTech: How does the development of new DPI devices affect the capsule requirements?
ACG: Improvement within capsule-based inhalers is a dynamic research area. The first marketed DPI, Spinhaler, was produced by Fisons in the late 1960s and used two pins to create opposing holes in the side wall of the body of a gelatin capsule; since then, many new devices have successfully reached the market. These include the Handihaler (Boehringer), Cyclohaler (Pharmachemie), Turbospin (Forest), and Ultibro (Novartis). The two main improvement directions in devices are obtaining lower resistance devices (lower ratio of pressure drop/flow) and evaluation of new materials for coating pins to reduce friction during the puncturing process. These new materials will improve puncture performance but also will help solve static electricity issues. Every time a new device requires higher spinning speeds, static electricity must be addressed. Additionally, due to the complex chemical structures of new APIs, new internal lubricants must be developed.