Powder Inhalers

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Introduction

Today there are essentially two types of DPIs, those that use drug filled into discrete individual doses, e.g., either a gelatin capsule or a foil-foil blister, and those that use a reservoir of drug that meters out doses when required. Both are now widely available around the globe and are gaining broad acceptance. There is clearly considerable interest in these devices because they do not require CFC propellants to disperse the drug and, as such, can be regarded as ozone-friendly delivery systems. Furthermore, although these devices do overcome the need for coordination of actuation and inspiration because they are essentially breath actuated, this is also one of their disadvantages. It is known that some DPIs require inspiratory flowrates of 60L/min [48,49] to effectively deaggregate the powder. This certainly cannot always be achieved by all asthmatic patients, particularly infants. This section discusses each of these types of device in turn and some of the common themes in relation to developing formulations for use in such devices (see Fig. 6).

Unit-Dose Devices

Single-dose powder inhalers are devices in which a powder-containing capsule is placed in a holder. The capsule is opened within the device and the powder is inhaled. The capsule residue must be discarded after use and a new capsule inserted for the next dose. The concept of the Spinhaler™ was first described in the early 1970s by Bell and colleagues [50], who had developed this device for the administration of powdered sodium cromoglycate. Briefly, the drug mixture, which often includes a bulk carrier to aid powder flow, is prefilled in a hard gelatin capsule and loaded into the device. After activation of the device, which pierces the capsule, the patient inhales the dose, which is dispensed from the vibrating capsule by means of inspired air.

A similar device (Rotahaler™, GlaxoSmithKline) has also been available for many years, delivering salbutamol and beclomethasone dipropionate powders. Here, the drug mixture is again filled in a hard capsule, and

Different Types Dry Powder Inhaler
Figure 6 Types of DPIs.

the capsule is inserted into the device; however, the capsule is broken open in the device, and the powder is inhaled through a screened tube [51]. Another device that dispenses drug loaded into hard gelatin capsules (fenoterol) is the Berotec Inhalator™ (Boehringer Ingelheim) [52]. Several introductions of single-dose DPIs have occurred over the past few years using similar designs (e.g., Aerolizer™—Novartis; Handihaler™—Boehringer Ingelheim).

Single-dose devices have performed well in clinical use for over 30 years. However, one criticism of these devices is the cumbersome nature of loading, which may not be easily accomplished if a patient is undergoing an asthma attack and requires immediate delivery of drug. This is clearly pertinent to devices that deliver short-acting bronchodilators. In addition, elderly patients may not have the manual dexterity to accomplish all the necessary maneuvers. Hence there has been considerable focus on developing multidose devices.

Multidose Devices

The development of multidose DPIs was pioneered by A. B. Draco (now a division of AstraZeneca) with their Turbuhaler [53]. This device is truly a metered-dose powder delivery system. The drug is contained within a storage reservoir and can be dispensed into the dosing chamber by a simple back-and-forth twisting action on the base of the unit (Fig. 7). The device is capable of working at moderate flowrates and also delivers carrier-free particles [54]. However, one of the drawbacks of the Turbuhaler has been the fact that it has

Turbuhaler

Figure 7 Components of the Turbuhaler, a multidose dry powder inhaler. (1) mouthpiece with insert, (2) bypass air inlet, (3) inhalation channel, (4) air inlet, (5) desiccant store, (6) window for dose indicator, (7) dose indicator, (8) storage unit for drug compound, (9) dosing unit, (10) operating unit, (11) turning grip.

Figure 7 Components of the Turbuhaler, a multidose dry powder inhaler. (1) mouthpiece with insert, (2) bypass air inlet, (3) inhalation channel, (4) air inlet, (5) desiccant store, (6) window for dose indicator, (7) dose indicator, (8) storage unit for drug compound, (9) dosing unit, (10) operating unit, (11) turning grip.

a highly variable delivery at different flowrates. This has also been the major criticism of several recently developed reservoir-type powder devices (e.g., Clickhaler™—ML Laboratories).

To address issues associated with a need for multiple dosing and consistent performance, Glaxo developed the Diskhaler™ [55], which was used to deliver a range of drugs, including salbutamol and beclomethasone. This device uses a circular disk that contains either four or eight powder doses on a single disk. This typically would be treatment for one to two days. The doses are maintained in separate aluminum blister reservoirs until just before inspiration. On priming the device, the aluminum blister is pierced, and the contents of the pouch are dropped

Dry Powder Inhaler Devices Pictures
Figure 8 Schematic of the Diskus™ powder inhaler.

into the dosing chamber. This product had limited commercial success and was superceded in the late 90's by the Diskus™. This device (see Fig. 8) is a true multidose device, having 60 doses in a foil-foil aluminum strip that is opened only at the point just prior to patient inspiration [56]. Consistent performance [57] and broad patient acceptance has allowed the Diskus™ to become the gold standard of multidose powder delivery devices.

Formulation Aspects

Dry powder formulations either contain the active drug alone or have a carrier powder (e.g., lactose) mixed with the drug. The drug particles must be of sufficiently small aerodynamic diameter to make it to and deposit on the airways. Micronized dry powder can be inhaled and deposited in the airways effectively from DPIs by patients with adequate breathing capacity because they can pull sufficient air through the device. However, young children, some patients with severe asthma, and elderly COPD patients may not always be able to achieve adequate inspiratory flow to ensure optimal medication delivery from DPIs.

Brown [58] alluded to the complexities involved in the design and development of a DPI. In much the same way as for an MDI, the combination of formulation (drug and carrier), the way that it is presented to the device, and the design of the dosing device itself all contribute to the overall performance of the dosage form. The requirement to use micronized drug with small (ideally less than 5.0-mm) particles, to achieve good aerodynamic properties of the dispersed powder, is confounded by the need to develop formulations that fill easily and accurately [59]. It is also important that changes in the physical nature of the formulation on transportation and storage not adversely affect the product performance. This needs to be investigated during formulation development. The inclusion of a carrier (often lactose) can aid in the handling of the formulation and may impart some aerodynamic benefits also. A further factor that aids in the design of optimal formulations is a close interaction of preformulation scientists and process chemists to provide materials (active drug) that have the desirable physical properties. This then allows delivery systems to be designed in which the drug forms stable aggregates that can be readily handled and are easily dispersed in the dosing device. However, there is still likely to be a need to achieve sufficient inspiratory flowrates in order to attain good respirable doses [60].

Peart and Clarke [4] in 2002 reviewed extensively the range of DPI developments, in terms of both device and formulation work that has been undertaken in the preceding decade. This is clearly an active area of interest for scientists as they strive to develop efficient delivery systems that do not contain environmentally harmful propellants. The goal of delivering micronized powders is a challenging one. Because of their very nature, these types of powders are highly cohesive. Their high interparticulate forces make them difficult to deaggregate, hence the need for high inspiratory flowrates and turbulent airflow within DPIs. Inclusion of a carrier may aid the deaggregation process, but it can also lead to problems with absorption of atmospheric moisture. Controlled temperature and humidity studies of salt forms and lactose (or other suitable carrier) combinations are essential during formulation development. In the Turbuhaler™, the effects of moisture uptake are moderated by the inclusion of a desiccant (see Fig. 7).

In 1988 Vidgren and colleagues [61] showed that spray-dried particles of disodium cromoglycate had better (at least in vitro) aerodynamic properties (i.e., a higher fraction of the dose in a smaller-size range) than micronized material, and others have continued these investigations using other methods of particle generation [61]. Staniforth et al. [62] have looked at various techniques to improve formulation performance by the development of tertiary mixtures. All the formulation development work is typically focused on achieving better aerosol performance.

Much interest has been focused recently on developing delivery systems that deaggregate the powder [63], for this effectively minimizes formulation development work. Some of these systems are extremely complex in operation and may prove difficult to achieve in everyday operations. In addition, some designs that have already been achieved (e.g., Nektar Therapeutics' Enhance™

device for the delivery of inhaled insulin) are likely to be bulky and too large to be portable.

In summary, DPIs are a widely accepted inhaled delivery dosage form, particularly in Europe, where they currently are used by approximately 40% of asthma patients, for the delivery of medications used to treat asthma and COPD. They may find use in a much broader spectrum of diseases as targeted delivery to the lung begins to be more widely accepted. Their lack of propellants makes them a desirable, environmentally friendly alternative.

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