Turbuhaler^® and Diskus™/Accuhaler™ are the most widely used dry powder inhalers in the world and are very different devices. Turbuhaler^® delivers a larger proportion of the labelled dose (around 25-35%) to the lung than Diskus™/Accuhaler™, which delivers less than half this amount (around 10-15%). Furthermore, decreased lung deposition has been reported in patients with moderate to severe asthma using Diskus™/Accuhaler™ while Turbuhaler^® is unaffected. Increased drug deposition in the lung with Turbuhaler^®, and hence reduced deposition in the throat, results in lower incidences of local side effects (candidiasis and dysphonia) compared with corticosteroid drug delivered via Diskus™/Accuhaler™. The presence of carrier particles with active drug in Diskus™/Accuhaler™ means that dose proportionality is harder to achieve and the product is more sensitive to high humidity, unlike Turbuhaler^®.

Reference

Borgström L, et al. Idealhalers or realhalers? A comparison of Diskus and Turbuhaler. Int J Clin Pract 2005;59(12):1488-95.

The fine particle fraction (FPF) is often expressed as a fraction of the labelled dose to allow a dose-normalised comparison of different drugs, strengths and devices. The FPF for currently marketed dry powder inhalers differs widely, ranging from 10-60% of the delivered dose. Lower FPFs are generated by products that contain a pharmaceutical formulation that is unable to generate a high FPF at inhalation and use inhalers that do not have efficient deaggregation mechanisms. Diskus™/Accuhaler™ is an example of a dry powder inhaler that delivers a low FPF - the drug is combined with a lactose carrier that has a low capacity for releasing fine particles. In addition, the dose released from the blister cavity into the inhaled air stream is not passing any steps for deaggregation before reaching the patient, which results in less efficient deaggregation. Inhalers such as Turbuhaler^®, which contain pharmaceutical formulations coupled with efficient deaggregation mechanisms reach higher FPFs. At inhalation, the spheronised particles leaving the dosing disc of Turbuhaler are efficiently deaggregated in the spiral shaped channels of the mouthpiece resulting in high FPF reaching the patient (Borgström et al, 2005). For example, in one study budesonide Turbuhaler^® delivered a FPF of 44% in 8-year-old children but fluticasone Diskus™/Accuhaler™ only delivered 20% (Bisgaard et al, 1998).

An ordered mixture and a co-spheronised formulation. The active drug particles are of the same size, while the lactose components are of very different size in the two formulations.

References

Bisgaard H, et al. Fine particle mass from the Diskus inhaler and Turbuhaler inhaler in children with asthma. Eur Respir J 1998;11:1111-5.

Borgström L, et al. Idealhalers or realhalers? A comparison of Diskus and Turbuhaler. Int J Clin Pract 2005;59(12):1488-95.

Different inhalers have different inbuilt resistances and the resistance in Diskus™/Accuhaler™ is slightly lower than that of Turbuhaler^®. This means that when a patient inhales with the same effort via Diskus™/Accuhaler™ or Turbuhaler^® the inhalation flow will be slightly higher with Diskus™/Accuhaler™ than with Turbuhaler^®. This does not mean that it is easier to inhale via Diskus™/Accuhaler™ than via Turbuhaler^®, only that the resulting inhalation flow will differ.

The delivery of the fine particle fraction (FPF) from Turbuhaler^® is more flow dependent than from Diskus™/Accuhaler™, but even at an inspiratory flow of 30 L/min Turbuhaler^® delivers a higher FPF than Diskus™/Accuhaler™. Inspiratory flow is one factor among many that can affect the delivery characteristics of dry powder inhalers.

There are no direct comparisons between Turbuhaler^® and Diskus™/Accuhaler™ with regard to the influence of peak inhalation flow on the clinical efficacy.

For Turbuhaler^® there are studies showing that when Bricanyl^® is inhaled at a low flow rate, 30 L/min, and at a typical flow, 60 L/min, no difference in FEV₁ was seen (figure) (Pedersen et al, 1990). Terbutaline was used as a model substance as the effect can be measured immediately after the first dose. (This in contrast to inhaled steroids where a number of doses have to be given to reach full effect.)

The same study showed that patients having a measurable clinical effect when inhaling Bricanyl^® via Turbuhaler^® at the extremely low PIF of 13 L/min (Pedersen et al, 1990) (see figure). More or less all patients, including those reporting at the emergency ward with an exacerbation, are capable of generating a PIF of at least 30 L/min when inhaling via Turbuhaler^®.



Forced expiratory volume in 1 second (FEV₁) after inhalation of 0.25 mg terbutaline via Turbuhaler^® at different flow rates in children with asthma. At 5 hours terbutaline was inhaled via Nebuhaler^® (Pedersen et al, 1990).

For Diskus™/Accuhaler™ there is only one published study investigating the difference in effect after using Diskus™/Accuhaler™ at different peak inspiratory flow rates, 30 and 90 L/min (Broeders et al, 2003). Also in this study there was no significant difference in effect between the two inhalation flows.

Collectively, for modern dry powder inhalers, such as Turbuhaler^® and Diskus™/Accuhaler™, the peak inhalation flow does not seem to have any significant impact on the clinical efficacy.

References

Broeders ME, et al. Inhalation profiles in asthmatics and COPD patients: reproducibility and effect of instruction. J Aerosol Med 2003;16:131-41.

Pedersen S, et al. Influence of inspiratory flow rate upon the effect of a Turbuhaler. Arch Dis Child 1990;65:308-10.

Typically, Turbuhaler^® delivers approximately 25-35% of the labelled dose to the lung and Diskus™/Accuhaler™ less than half this amount, i.e. a two to three fold difference. In a comparative study of children with asthma, the lung deposition (% of the labelled dose) for Pulmicort^® Turbuhaler^® was 30% and 8% for fluticasone Diskus™/Accuhaler™ (Agertoft and Pedersen, 2003). In another study, the corresponding values were 36% for Pulmicort^® Turbuhaler^® and 13% for fluticasone Diskus™/Accuhaler™ in a group of healthy adults, and 38% for Turbuhaler^® and 14% for Diskus™/Accuhaler™ in patients with asthma (Thorsson et al, 2001).

The substantial difference in lung deposition between Diskus™/Accuhaler™ and Turbuhaler^® is due both to a difference in the mechanical properties of each inhaler and as well as differences in the pharmaceutical formulations used with each system. The two to three fold difference in lung deposition between Turbuhaler^® and Diskus™/Accuhaler™ is of the same magnitude as the difference in fine particle fraction (FPF) between the two inhalers, indicating that FPF may be a good predictor of lung deposition. Asking et al (2001) analysed different strengths of the two inhalers and reported a FPF of 44-46% for Pulmicort^® Turbuhaler^® and 14-24% for fluticasone Diskus™/Accuhaler™.

References

Agertoft L, Pedersen S. Lung deposition and systemic availability of fluticasone Diskus and budesonide Turbuhaler in children. Am J Respir Crit Care Med 2003;168:779-82.

Asking L, et al. Flutide Diskus less consistent than Pulmicort Turbuhaler with respect to in vitro fine particle dose proportionality. Am J Respir Crit Care Med 2001;163:A441.

Thorsson L, et al. Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®. Br J Clin Pharmacol 2001;52:529-38.

In a study of patients with moderate to severe asthma (FEV₁ 49% of predicted), only 57% of the dose of fluticasone Diskus™/Accuhaler™ inhaled by healthy controls was available in the airways to the asthmatic patients whereas all of the dose (actual value 112%) of Pulmicort^® Turbuhaler^® was available to the asthma group compared with healthy controls (Harrison and Tattersfield, 2003). Further studies with fluticasone have shown similar decreases of lung deposition (down to 47% and 63%) in patients with moderate to severe asthma (Brutsche et al, 2000; Singh et al, 2003) Thus, Turbuhaler^® is unaffected by lung function, but Diskus™/Accuhaler™ is affected when delivering its respective inhaled steroid.

Read more about the explanation for lung deposition being dependent on lung function.

References

Brutsche MH, et al. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: A randomised crossover study. Lancet 2000;356:556-61.

Harrison TW, Tattersfield AE. Plasma concentrations of fluticasone propionate and budesonide following inhalation from dry powder inhalers by healthy and asthmatic subjects. Thorax 2003;58:258-60.

Singh SD, et al. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in chronic obstructive pulmonary disease. Br J Clin Pharmacol 2003;55:375-81.

As stated in the previous sections, one of the most important factors that determine the clinical effect of an inhaled drug is the amount of drug that reaches the lungs. Clearly, a large variability in lung deposition could cause a corresponding variability in the exerted effects.

In vitro analyses, conducted under strict, standardised conditions, primarily ascertain the quality of a manufactured product. The absolute amount and variability of drug leaving the inhaler are typical in vitro parameters. In vivo analyses, however, enable the outcome in the clinical situation to be assessed. The measured in vitro variability may account for only a small portion of the overall variability observed in the clinical situation.

In two studies evaluating the variability of in vivo lung deposition, the higher lung deposition for budesonide Turbuhaler^® compared with fluticasone Diskus™/Accuhaler™ was associated with a lower variability in both healthy subjects and patients with asthma, including children (Agertoft and Pedersen, 2003; Thorsson et al, 2001, 2003 and Table).

In conclusion, when examined under the conditions that are relevant to clinical use, Turbuhaler^® showed less variability in lung deposition than Diskus™/Accuhaler™ in healthy subjects as well as in adult patients and children with asthma.

Lung deposition and variability of lung deposition of budesonide Turbuhaler^® and fluticasone Diskus™/Accuhaler™.

References

Agertoft L, Pedersen S. Lung deposition and systemic availability of fluticasone Diskus and budesonide Turbuhaler in children. Am J Respir Crit Care Med 2003;168:779-82.

Thorsson L, et al. Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®. Br J Clin Pharmacol 2001;52:529-38.

Thorsson L, Edsbäcker S. Less variability in lung deposition of budesonide via Turbuhaler^® than of fluticasone via Diskus^®/Accuhaler^® and pMDI in adults. Am J Respir Crit Care Med 2003;167(7 Suppl):A896.

Particles less than 5 µm are sufficiently small to have a greater probability to penetrate the throat and reach the lungs, thus producing a clinical effect at the target organ. In contrast, particles greater than 5 µm have high inertia and do not normally pass the throat (see figure). This larger fraction does not produce a clinical effect but can result in local side effects in the throat before being swallowed. While none of the currently marketed inhalers deliver the complete dose as fine particles, a high fraction of larger particles can result in increased local side effects; hence, differences between inhaler devices are clinically important.

In addition, it is also possible for deposition to occur on the teeth and tongue; this is obviously undesirable as it reduces the amount of drug reaching the lungs and can also increase the variability of lung deposition. Turbuhaler^®, like most dry powder inhalers have a mouthpiece that naturally fits the lips and teeth at inhalation. The mouthpiece of the Diskus™/Accuhaler™, however, is small and short. Teeth and tongue deposition can be significant in some patients while in others it might be difficult to assure a tight seal between the mouthpiece and the lips.

Asthma is a variable disease and patients sometimes need to change the strength of their medication. To allow a controlled change between different doses the fine particle fraction (FPF) must be the same irrespective of the drug dose. For example, two inhalations of a 50 µg dose should deliver the same FPF as one inhalation of a 100 µg dose. Dose proportionality is important with respect to both the desired and the undesired effects.

For dry powder inhaler formulations that are based on a co-spheronisation of 2-4 µm primary particles to larger aggregates, proportionality between the strengths is easily achieved. In those formulations of Turbuhaler where lactose is used as diluter, the lactose particles are of the same size as the primary drug particles. Although the balance between active drug and lactose does vary between different strengths, the FPF stays the same (Figure) (Asking et al, 2002).

For dry powder inhaler formulations that use carrier-based systems, such as Diskus™/Accuhaler™, dose proportionality is harder to achieve. In Diskus™/Accuhaler™ formulations, the size of the lactose carrier particles range from 50-150 µm. These carrier particles have energy rich active sites on their surface and the 2 to 4 µm drug particles will adhere to these sites. The drug particles that are strongly bound to the carrier particle will not be aerosolised at inhalation. Therefore, a low-dose formulation will release, at aerosolisation, only a small proportion of the added drug particles. Because the same amount of carrier particles are used for the different strengths of the same formulation, a higher dose will have a smaller proportion of drug particles tightly bound to the carrier. Hence at inhalation, a larger fraction of the drug particles will be aerosolised and the relative FPF will increase with increasing dose. This has been observed for the fluticasone Diskus™/Accuhaler™ formulation (figure) (Asking et al, 2002) and fluticasone + salmeterol Diskus™/Accuhaler™ (Lipniunas et al, 2003).

Fine particle dose, as percentage of nominal dose, for different strengths of fluticasone Diskus™/Accuhaler™ and budesonide Turbuhaler^®.

References

Asking L, et al. Flutide Diskus less consistent than Pulmicort Turbuhaler with respect to in-vitro fine particle dose proportionality. Eur Respir J 2002;18:157s.

Lipniunas P, et al. Dose proportionality of in vitro fine particle dose for dry powder inhaler combination products. Eur Respir J 2002;20:541s.

Humidity, during storage and use is another important factor that can influence the quality of the aerosol dose from a dry powder inhaler. Dry powder formulations, which contain lactose or a hygroscopic active drug will eventually be degraded at storage if not protected.

Turbuhaler^® contains an internal drying agent to protect the drug from humidity at storage and absorbing the humidity in the inhaler during use.

A recent study have investigated the effect of storage conditions on the in vitro as well as the in vivo performance of Symbicort^® Turbuhaler^® and Seretide™ Diskus™/Accuhaler™ (Borgström et al, 2005). Storage for 3 months at 40°C and 75% relative humidity had no effect on the fine particle fraction (FPF) of budesonide and formoterol delivered by Symbicort^® Turbuhaler^®, whereas with Seretide™ Diskus™/Accuhaler™ the FPF of fluticasone and salmeterol were reduced to 56% and 54%, respectively.

In the in vivo part of the study it was shown that the hot and humid storage reduced the lung deposition of fluticasone from Seretide™ Diskus™/Accuhaler™ down to about 50%. Lung deposition of budesonide from Symbicort^® Turbuhaler^® was unaffected by the hot and humid storage (Figure).



Effect of storage of Symbicort^® Turbuhaler^® and Seretide™ Diskus™/Accuhaler™ for 3 months under hot and humid conditions on the fine particle dose and delivered dose of inhaled steroid. (Data from Borgström et al, 2005).



Relative lung deposition of budesonide and fluticasone after storage of Symbicort^® Turbuhaler^® and Seretide™ Diskus™/Accuhaler™ for 3 months under hot and humid conditions or dry conditions at room temperature. (Data from Borgström et al, 2005).

References

Borgström L, Lipniunas P. Symbicort^® Turbuhaler^® is not affected by storage in hot and humid conditions. A clinical pharmacokinetic comparison with Seretide™ Diskus™. Am J Respir Crit Care Med 2003;167(7 Suppl):A896.

Borgström L, et al. An in vivo and in vitro comparison of two powder inhalers following storage at hot/humid conditions. J Aerosol Med 2005;18(3):304-10.

As discussed earlier, the clinical outcome is often dependent on the study design used, and caution is needed when interpreting the results of inappropriately designed studies. (Read more about the clinical efficacy of Turbuhaler^®).

In a double-blind, double-dummy dose reduction study, 197 adult patients with asthma stabilised during treatment with BDP 2000 µg/day were randomised to receive Pulmicort^® Turbuhaler^® or fluticasone Diskus™/Accuhaler™ 800 µg/day and the dose was halved at 5-week intervals if asthma control was maintained (Kuna et al, 2003). The median minimal effective dose was 400 µg in both groups, and there was no apparent difference in the distribution of doses between the groups.

A similar relation has been shown between Pulmicort^® Turbuhaler^® and fluticasone Diskhaler™, again using a dose-reduction design.

Some studies have directly compared the clinical effectiveness of Symbicort^® Turbuhaler^® and Seretide™ Diskus™/Accuhaler™. In a study by Aalbers et al (2004), symptomatic patients received either fixed dose (FD) salmeterol/fluticasone (50/250 µg bid), fixed dose budesonide/formoterol (2 inhalations of 160/4.5 µg bid) or adjusted dose budesonide/formoterol (2 inhalations of 160/4.5 µg bid or 160/4.5 µg bid that could be adjusted to 4 inhalations bid for 7-14 days if a asthma worsening occurred (AMD))

Budesonide/formoterol AMD increased the odds of achieving a well-controlled asthma week compared with budesonide/formoterol FD (odds ratio 1.335; 95% CI: 1.001, 1.783; p=0.049) despite a 15% reduction in average study drug use. Furthermore, budesonide/formoterol AMD patients had a lower exacerbation rate over the study: 40% lower vs. salmeterol/fluticasone FD (p=0.018); 32% lower vs. budesonide/formoterol FD (NS) (figure); and used less reliever medication: 0.58 vs. 0.92 occasions/day for budesonide/formoterol FD (p=0.001) and 0.80 occasions/day for salmeterol/fluticasone FD (p=0.011).

This suggests that adjustable maintenance dosing with Symbicort^® Turbuhaler^® provides more effective asthma control by reducing exacerbations and reliever medication usage.



Number of exacerbations in asthma patients receiving either Symbicort^® Turbuhaler^® as adjustable maintenance dosing (AMD) or fixed dosing (FD) or Seretide™ Diskus™/Accuhaler™ FD. (Data from Aalbers et al, 2004).

Reference

Aalbers R, et al. Adjustable maintenance dosing with budesonide/formoterol compared with fixed-dose salmeterol/fluticasone in moderate to severe asthma. Curr Med Res Opin 2004;20:225-40.

As discussed earlier, high oropharyngeal deposition can result in increased local side effects. Long-term local side effects were evaluated in a 7-months comparison between Symbicort^® Turbuhaler^® and Seretide™ Diskus™/Accuhaler™. Patients received either fixed dose (FD) salmeterol/fluticasone (50/250 µg bid), fixed dose budesonide/formoterol (2 inhalations of 160/4.5 µg bid) or flexible dose budesonide/formoterol (2 inhalations of 160/4.5 µg bid or 160/4.5 µg bid that could be adjusted to 4 inhalations bid for 7-14 days if a asthma worsening occurred (AMD)) (Andersson et al, 2004).

Candidiasis and dysphonia were considerably lower with budesonide/formoterol than salmeterol/fluticasone (see figure), and these values were lowered further with flexible dosing of budesonide/formoterol. The difference in incidences of both candidiasis and dysphonia between salmeterol/fluticasone Diskus™/Accuhaler™ and budesonide/formoterol Turbuhaler^® is the result of reduced particle deposition in the throat with budesonide/formoterol.



Proportion of asthma patients reporting candidiasis or dysphonia during treatment with either Symbicort^® Turbuhaler^® as adjustable maintenance dosing (AMD) or fixed dosing (FD), or Seretide™ Diskus™/Accuhaler™ FD. (Data from Andersson et al, 2004).


Reference

Andersson T, et al. High nonrespiratory fraction of drug delivered by Diskus compared with Turbuhaler correlates with elevated side-effect levels. Eur Respir J 2004;24(Suppl 48):584S.