Dry powder inhalers: challenges and goals for next generation therapies

Dry powder inhalers (DPIs) have advanced significantly over the past 10–15 years.¹ This has been driven by the need to reformulate pressurized metered dose systems to chlorofluorocarbon (CFC)-free systems using hydrofluoroalkanes and the potential to deliver a wider range of therapeutics to the respiratory tract (through improved stability and greater dose choice).

Apart from medication that specifically targets asthma, other therapies under investigation that use DPI systems include both local delivery (for example, mucolytics, antibiotics, antituberculosis and anticancer drugs) and systemic delivery (for example, insulin, analgesics for cancer pain and drugs for erectile dysfunction).^2–4 In simple terms, the formulation of a DPI generally involves:

• The production and characterization of a powder suitable for respiratory deposition.^5,6

• The formulation with or without excipients in a device.⁷

The system is characterized by aerosol performance and stability, and optimized through empirical observation. Although highly simplified here, these key stages of development will be discussed in this article.

Primary API

Arguably the nature of the active pharmaceutical ingredient (API) particles is the key to effective DPI delivery. The conventional way to produce a respirable size range API (<5 μm aerodynamic diameter) involves the crystallization from a solution followed by high-energy milling. Although this method is still the most common way to produce micronized APIs, it is not necessarily the most attractive as it requires a multistep process, results in particulates with ill-defined geometries and leads to questions concerning polymorphism and the degree of amorphous content.

Key points

The deliberate control of the API's physical form, geometry and surface composition can be dated back to the 1980s when Gonda and co-workers successfully used elongated particles for their advantageous aerodynamic behaviour,^5–7 and particles coated with hydrophobic additives for the reduction of hygroscopic growth in the airways after inhalation.^8,9 Recently, there has been renewed interest in using engineered particles for DPI formulation to improve the powder dispersibility. The objective is to make 'nonsticky' particles that have a small aerodynamic diameter. The approach includes manipulation of the particle size (including nanoparticles), shape, density, surface morphology and other surface properties.^10,11

Single-step production methods have been developed with spray drying being the prominent one for inhaled insulin (approved by FDA) as well as inhaled mannitol, which was approved by the Australian Therapeutic Good Administration (TGA). Furthermore, the addition of binary/ternary components into the initial spray dryer solution may allow increased physical stability in primarily amorphous systems and/or the production of specific morphologies with, for example, improved aerosolization efficiency and reduced density. Other methods of API production include supercritical fluid (SCF) precipitation, high gravity precipitation and production through ultrasonic crystallization.^12,13

Formulation considerations

The formulation of many APIs requires the addition of binary or ternary agents after production to improve powder flow, improve dose reproducibility and act as a diluent for highly active compounds to fulfil the regulatory requirements and produce the anticipated clinical outcome. The traditional approach of powder blends containing the API mixed with lactose as a carrier is still most widely used for DPI products. Furthermore, in recent years, this approach has not only been used for dilution and improving the flowability, but also for enhancing the dispersibility of the micronized API.

There have been significant advances, especially in understanding the role of carrier properties on the aerosol performance of the API. For example, early work suggested the roughness and the specific size of lactose carriers may be related to the aerosolization performance of an API through variation in contact geometry.^14–17

Such observations were substantiated and built upon in recent work, which suggests a complex interplay between performance and the degree of fine lactose,^18–20 the macroscopic morphology,^16,17,21,22 the presence of 'active sites',^14,22,23 and aerosol API performance. The exact mechanism of adhesion and drug liberation during aerosolization is still not clearly understood and is a major focus among researchers within the field.

Clearly, by controlling such parameters, the aerosolization performance of a particular API may be 'fine tuned' to acquire the chosen respiratory deposition, while maintaining product stability. Subsequently, many relevant carrier engineering technologies have been reported to improve specific performance parameters.

Controlled crystallization

Some of the key developments include the improvement of API aerosolization performance by controlled crystallization of the carrier:

Crystal shape. Lactose crystallized from Carbopol gel achieves more regularly shaped lactose crystals with a smoother surface compared with the control lactose, resulting in higher efficiency and reproducibility of drug delivery by DPIs.²⁴

Surface smoothing. The engineering of lactose carrier surfaces using a proprietary particle smoothing process results in significant differences in surface morphology when compared with the 'as supplied' starting material, and leads to improved aerosolization efficiency from commercially available DPIs.^25,26

Controlled etching of the carrier particles to reduce variation in API adhesion. Treatment of the lactose carrier by solution-phase variable temperature dissolution with a suitable liquid that can control the particle surface dissolution, combined with the removal of fines produce materials that increase aerosolization of the active from a single dose inhaler.²⁷

Addition of ternary agents. Addition of ternary agents, such as magnesium stearate and/or L-Leucine, reduce API carrier adhesion; that is, the use of spray-drying produces a specific physical form of L-Leucine that is suitable as a flow aid during aerosolization.²⁸

Carrier fines. Addition of carrier fines can reduce the variation of API-carrier adhesion by filling active sites and/or by forming complex binary/ternary mixtures; that is, investigating the order of mixing of ternary components, examining particle interactions between drug and fine excipient particles (intrinsic or externally added ternary particles); and investigating adhesional properties of the lactose carrier surface using specific techniques such as the atomic force microscopy (AFM) colloid probe technique (CPT).^18,19,28,29

DPI device

The inhaler device is as important as the powder formulation for the successful development of DPI products. Powder dispersion in DPI devices is accomplished either passively by the patient's own inspiration, or actively by a suitable component, such as an electronic vibrator or impeller, in the DPI device. Because micronized particles are difficult to deaggregate, the efficacy of passive DPI devices depends critically on a patient's inspiratory flow rate.

As a result of the recent focus on tightening regulatory requirements, it is desirable for the performance of (breath-actuated) passive inhalers to have minimal dependence on the patient's inspiratory air flow. Furthermore, these DPI devices are now much more sophisticated than they used to be when only single-dose, capsule-loading systems existed.

From the development perspective, 'passive' multidose DPIs fall into two main categories. They either measure the dose from a powder reservoir or they disperse individual doses that are premetered into blisters by the manufacturer. In general, the premetered drug-in-blister/capsule approach is easier to develop because the reproducibility of the metered dose can be ensured during the drug formulation and packaging, but for the purpose of this article the authors will mainly focus on novel multidose devices.

One of the most recently marketed multidose DPI products in the US, Asmanex Twisthaler (Schering-Plough, Kenilworth, NJ, USA), for the delivery of mometasone furoate has shown highly reproducible results on emitted dose and fine particle fraction (FPF) using a patented agglomerate formulation.³⁰ In the Twisthaler, the DPI nozzle comprises two parts: a lower swirl chamber and upper chimney in the mouthpiece. A patented fluted chimney design was used to produce a stronger vortex with an increased number of particle collisions with the chimney for deagglomeration.³¹

The Novolizer (Meda Pharma BV, Amstelveen, The Netherlands) is a multidose DPI device already marketed in Europe.³² The Novolizer works on the cyclone principle and air classifier technology. These are robust concepts involving both centrifugal force and drug force acting on the particles swirling in a cylindrical chamber (cyclone), which coupled with collision force achieves drug particle detachment from carrier surfaces.³³

Another multidose device using a cyclone (in the mouthpiece) for drug deagglomeration is the Next DPI.³⁴ The Otsuka DPI (ODPI [Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan]) disperses a freeze-dry cake containing the active drug by inspiratory air flow of the patient during use.³⁵ This is particularly suitable for delivering biological products, as each dose is individually contained in a vial which eliminates problems caused by contamination and microbial growth.

Other recent devices include the Acu-Breathe multidose DPI by Respirics Inc. (Raleigh, NC, USA),³⁶ a prototype DPI by Oriel Therapeutics Inc. (Research Triangle Park, NC, USA) using a piezoelectric polymer, which vibrates to deliver the powder,³⁷ and a patented powder dispensing device based on the rotating fluidized bed principle.³⁸ While most DPIs deliver relatively low doses of drug, the Actispire by Britannia Pharmaceuticals (Redhill, UK) is suitable for high dose delivery (e.g., 20–250 mg of a synthetic lung surfactant).³⁹ This device uses a pressurized gas to aerosolize micronized powder contained in the individual vial.

There are numerous studies comparing the in vitro performance of DPIs, but few provide insights into the mechanisms of powder dispersion in the inhaler devices. Such information is beneficial and would allow rational design of a more efficient inhaler with enhanced performance. The designs of the Twisthaler and the Next DPI were aided by computational fluid dynamics (CFD), but unfortunately, very little details were provided.^25,28

Recently, the Aerolizer (Figure 1) was investigated in a series of fundamental studies linking experimental powder dispersion data with CFD simulation of air flow in the inhaler.^40–43 These results provided a deeper understanding of how the inhaler performance is influenced by DPI design features, including the design of a grid, the presence of a capsule and the dimension of the air inlet — all these are common features present in DPIs.

Figure 1

Grid. The grid was found to have three functions:

• Helps straighten the air flow in the mouthpiece.

• Generates small eddies immediately above the grid in the mouthpiece.

• Allows high-velocity collision between the particles and the grid to occur. A high FPF can be achieved using a grid that will generate more energetic turbulence and higher frequency of particle–grid collision.

Capsule. A number of passive DPIs use a capsule to contain a unit dose, followed by emptying the powder into the air stream inside the inhaler after piercing the capsules. It was found that the presence of a spinning capsule in the Aerolizer significantly reduces the turbulence (i.e., the potential for powder deagglomeration). However, the dimension of the pierced hole in the capsule is critical because deagglomeration occurs when the powder is sheared through the holes when it is emptied from the spinning capsule.

Air inlet. All DPIs contain some form of air inlet to allow entrainment of air into the device for powder emptying and dispersion as the patient inhales. If the air inlet dimension for the Aerolizer is reduced, it takes longer for the air flow to be fully developed in the inhaler, and the capsule spins faster (as a result of the higher inlet air linear speed) to empty the powder out into the air stream sooner.

When the powder is emptied into the air stream before the air flow is fully developed, powder deagglomeration will be less effective, making the inhaler performance actually poorer with a smaller air inlet. This was observed for the Aerolizer operating at 60 and 90 L/min with a one-third or two-third inlet size. The results, therefore, highlighted the importance of synchronizing powder release and turbulence build-up in the inhaler.

The market is rapidly expanding and many novel inhalation devices are in development. Several companies are active in the area, including Aradigm, Batelle Pharma, Chrysalis Technologies, Boehringer-Ingelheim and MAP Pharmaceuticals.^44–51 All are developing 'active' inhalers that offer the advantage of dosing precision and an energy source to enable patient-independent, reproducible aerosol production.

Conclusion

Recent research into multidose DPIs has been presented in this article. The aerosolization performance of a DPI is a complex system that clearly requires more fundamental studies. It is anticipated that future development of DPI products will rely more on rational design of both the inhaler device and powder formulation properties to attain the optimal products.

Hak-Kim Chan Is professor of pharmaceutics

Paul M. Young Is a lecturer in pharmaceutics

Daniela Traini Is a lecturer all at the Faculty of Pharmacy, University of Sydney (Australia).

Matthew Coates Is a former PhD student at the Faculty of Pharmacy, University of Sydney (Australia) and currently senior scientist at Pfizer Ltd (UK).

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